Is LARGE1 p.Ser84Thr (c.251G>C) pathogenic?

LARGE1 p.Ser84Thr (c.251G>C) is classified Benign/Likely benign in LARGE1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0859); Low-frequency (popmax 1.64%, sas); Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6.

How common is LARGE1 p.Ser84Thr (c.251G>C) in the general population?

LARGE1 p.Ser84Thr (c.251G>C) is low-frequency (popmax 1.64%, sas) (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.Ser84Thr (c.251G>C)?

AlphaMissense predicts likely benign (score 0.0859) — an in-silico prediction, not a clinical call.

LARGE1 p.Ser84Thr

Q: What condition is associated with LARGE1 p.Ser84Thr (c.251G>C)?

LARGE1 p.Ser84Thr (c.251G>C) is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6, muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

c.251G>C · rs398124184 · VCV95173

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0859 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.64%, sas)

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	0.0859	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -2.92	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 4	GERP 2.1, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 111 kb · p 0.14 · regional, not allelic
Overall
CADD	22.8	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 1.64% South Asian · 1,490/91,076 alleles

Filtering AF 1.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.54%

Overall 0.097% 1,563/1,612,158 alleles · low-frequency exomes 1,468/1,459,786 · genomes 95/152,372 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.64%	61
Remaining individualsnot grpmax-eligible	0.0864%	1,157
Middle Eastern	0.0825%	1,212
African / African-American	0.00266%	37,537
East Asian	0.00223%	44,882
European (non-Finnish)	0.000932%	107,272

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.Ser84Thr
Coding: c.251G>C
MANE Select: NM_133642
dbSNP: rs398124184
Type: single nucleotide variant
Location: chr22:33650524 (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 84: the 'disordered' 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.Ser84= Conflicting classifications of pathogenicity ★ same residue
LARGE1 p.Ser84Ile 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

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-ser84thr (accessed [today's date]).

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