Is FIG4 p.Ser776Cys (c.2327C>G) pathogenic?

FIG4 p.Ser776Cys (c.2327C>G) is classified Uncertain significance in FIG4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-07-23). AlphaMissense: likely benign (0.2106); Ultra-rare (popmax 0.034%, sas); Associated with Inborn genetic diseases.

What condition is associated with FIG4 p.Ser776Cys (c.2327C>G)?

FIG4 p.Ser776Cys (c.2327C>G) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Ser776Cys (c.2327C>G) in the general population?

FIG4 p.Ser776Cys (c.2327C>G) is ultra-rare (popmax 0.034%, sas) (gnomAD).

What do computational predictors say about FIG4 p.Ser776Cys (c.2327C>G)?

AlphaMissense predicts likely benign (score 0.2106) — an in-silico prediction, not a clinical call.

FIG4 p.Ser776Cys

c.2327C>G · rs760215765 · VCV916877

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2106 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2106	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -9.28	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 4.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.33 · regional, not allelic
Overall
CADD	25.3	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 0.034% South Asian · 31/91,084 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00229% 37/1,613,894 alleles · ultra-rare exomes 35/1,461,714 · genomes 2/152,180 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.034%	2,938
Middle Eastern	0.0329%	3,040
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.000169%	590,019

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: FIG4
Protein: p.Ser776Cys
Coding: c.2327C>G
MANE Select: NM_014845
dbSNP: rs760215765
Type: single nucleotide variant
Location: chr6:109791522 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 776: the 'disordered' region

Full FIG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease type 4

Similar variants

FIG4 c.1040-1G>A Likely pathogenic ★★ same condition
FIG4 c.1584-1G>T Likely pathogenic ★★ same condition
FIG4 c.1948+1G>A Likely pathogenic ★★ same condition
FIG4 c.1949-10T>G Pathogenic/Likely pathogenic ★★ same condition
FIG4 c.2459+1G>A Pathogenic ★★ same condition
FIG4 c.877-2A>C Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Arg152Ter Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Arg183Ter Pathogenic/Likely pathogenic ★★ 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/fig4-p-ser776cys (accessed [today's date]).

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