Is LARGE1 p.Ser84Ile (c.251G>T) pathogenic?

LARGE1 p.Ser84Ile (c.251G>T) is classified Uncertain significance in LARGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-25). AlphaMissense: likely benign (0.1575); Ultra-rare (popmax 0.045%, amr); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Ser84Ile (c.251G>T)?

LARGE1 p.Ser84Ile (c.251G>T) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

How common is LARGE1 p.Ser84Ile (c.251G>T) in the general population?

LARGE1 p.Ser84Ile (c.251G>T) is ultra-rare (popmax 0.045%, amr) (gnomAD).

What do computational predictors say about LARGE1 p.Ser84Ile (c.251G>T)?

AlphaMissense predicts likely benign (score 0.1575) — an in-silico prediction, not a clinical call.

LARGE1 p.Ser84Ile

c.251G>T · rs398124184 · VCV464474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1575 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

muscular dystrophy-dystroglycanopathy type B6

Computational evidence

Protein change
AlphaMissense	0.1575	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -4.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
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	23.4	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 0.045% Admixed American · 27/60,014 alleles

Filtering AF 0.0317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.00186% 30/1,612,158 alleles · ultra-rare exomes 30/1,459,786 · genomes 0/152,372 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.045%	2,223
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000169%	589,995

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.Ser84Ile
Coding: c.251G>T
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 type B6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LARGE1 p.Ser84Thr Benign/Likely benign ★★ same residue
LARGE1 p.Ser84= Conflicting classifications of pathogenicity ★ 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-ser84ile (accessed [today's date]).

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