Is LARGE1 p.Arg77His (c.230G>A) pathogenic?

LARGE1 p.Arg77His (c.230G>A) is classified Uncertain significance in LARGE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0919); Very rare (popmax 0.00167%, amr); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Arg77His (c.230G>A)?

LARGE1 p.Arg77His (c.230G>A) is associated with muscular dystrophy-dystroglycanopathy type B6, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (ClinVar).

How common is LARGE1 p.Arg77His (c.230G>A) in the general population?

LARGE1 p.Arg77His (c.230G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about LARGE1 p.Arg77His (c.230G>A)?

AlphaMissense predicts likely benign (score 0.0919) — an in-silico prediction, not a clinical call.

LARGE1 p.Arg77His

c.230G>A · rs1402888044 · VCV902995

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy-dystroglycanopathy type B6

Computational evidence

Protein change
AlphaMissense	0.0919	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -9.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 2.1, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 111 kb · p 0.14 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,992 alleles

Overall 0.000186% 3/1,609,850 alleles · very rare exomes 2/1,457,616 · genomes 1/152,234 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,992
Finnishnot grpmax-eligible	0.00167%	60,004
European (non-Finnish)	8.47e-05%	1,179,949

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.Arg77His
Coding: c.230G>A
MANE Select: NM_133642
dbSNP: rs1402888044
Type: single nucleotide variant
Location: chr22:33650545 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.15 · 4 PDB

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

Disease context

muscular dystrophy-dystroglycanopathy type B6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

LARGE1 p.Arg77Gly Uncertain significance ★ ⚠ same residue
LARGE1 p.Arg77= Likely benign ★ 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-arg77his (accessed [today's date]).

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