Is LARGE1 p.Arg665His (c.1994G>A) pathogenic?

LARGE1 p.Arg665His (c.1994G>A) is classified Benign/Likely benign in LARGE1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1121); Low-frequency (popmax 1.16%, nfe); Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6.

How common is LARGE1 p.Arg665His (c.1994G>A) in the general population?

LARGE1 p.Arg665His (c.1994G>A) is low-frequency (popmax 1.16%, nfe) (gnomAD).

How is Walker-Warburg syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LARGE1 p.Arg665His (c.1994G>A)?

AlphaMissense predicts likely benign (score 0.1121) — an in-silico prediction, not a clinical call.

LARGE1 p.Arg665His

Q: What condition is associated with LARGE1 p.Arg665His (c.1994G>A)?

LARGE1 p.Arg665His (c.1994G>A) is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6, muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

c.1994G>A · rs1046166 · VCV95171

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1121 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.16%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

Computational evidence

Protein change
AlphaMissense	0.1121	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -8.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.025, phastCons 0.99
Regional constraint	o/e 0.74	unconstrained · MANE · 376 kb · p 7.6e-14 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.16% European (non-Finnish) · 13,738/1,180,024 alleles

Filtering AF 1.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.14%

Overall 0.929% 14,996/1,614,246 alleles · low-frequency exomes 14,086/1,461,870 · genomes 910/152,376 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	6.47%	15
European (non-Finnish)grpmax	1.16%	86
Remaining individualsnot grpmax-eligible	0.624%	160
South Asian	0.369%	271
Admixed American	0.273%	366
Middle Eastern	0.264%	379
African / African-American	0.21%	475
Finnishnot grpmax-eligible	0.205%	489
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,868
East Asian	0.00223%	44,888

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LARGE1
Protein: p.Arg665His
Coding: c.1994G>A
MANE Select: NM_133642
dbSNP: rs1046166
Type: single nucleotide variant
Location: chr22:33277139 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.15 · 4 PDB
Residue 665: a UniProt-annotated variant site (in); the 'glucuronyltransferase activity' region

Full LARGE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy type B6

For Walker-Warburg syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (United Kingdom)

Similar variants

LARGE1 p.Arg665Cys Uncertain significance ⚠ same residue
LARGE1 p.Arg95Ter Pathogenic ★★ same condition
LARGE1 p.Glu509Lys Pathogenic/Likely pathogenic ★★ same condition
LARGE1 c.*155C>T Uncertain significance ★★ same condition
LARGE1 p.Ala149Ser Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala252Val Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala478Thr Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala635Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/large1-p-arg665his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown