Is FIG4 p.Val654Ala (c.1961T>C) pathogenic?

FIG4 p.Val654Ala (c.1961T>C) is classified Benign in FIG4 (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0527); Common (popmax 69.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease.

What condition is associated with FIG4 p.Val654Ala (c.1961T>C)?

FIG4 p.Val654Ala (c.1961T>C) is associated with Charcot-Marie-Tooth disease, Yunis-Varon syndrome, Charcot-Marie-Tooth disease type 4J (ClinVar).

What do computational predictors say about FIG4 p.Val654Ala (c.1961T>C)?

AlphaMissense predicts likely benign (score 0.0527) — an in-silico prediction, not a clinical call.

FIG4 p.Val654Ala

Q: How common is FIG4 p.Val654Ala (c.1961T>C) in the general population?

FIG4 p.Val654Ala (c.1961T>C) is common (popmax 69.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1961T>C · rs9885672 · VCV137377

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.0527 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 69.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.0527	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -3.95	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 0.046	GERP -1.3, phastCons 0.001
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.33 · regional, not allelic
Overall
CADD	10.93	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 69.9% African / African-American · 52,266/74,792 alleles

Filtering AF 69.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 69.2%

Overall 21% 338,959/1,610,604 alleles · common exomes 287,471/1,458,520 · genomes 51,488/152,084 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	69.9%	1
South Asian	44.1%	2
East Asian	39.9%	3
Middle Eastern	31.2%	3
Admixed American	27.3%	4
Remaining individualsnot grpmax-eligible	24.9%	4
Ashkenazi Jewishnot grpmax-eligible	24.7%	4
Finnishnot grpmax-eligible	21.9%	5
Amishnot grpmax-eligible	18.8%	5
European (non-Finnish)	14.7%	7

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.Val654Ala
Coding: c.1961T>C
MANE Select: NM_014845
dbSNP: rs9885672
Type: single nucleotide variant
Location: chr6:109786314 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 654: a UniProt-annotated variant site (in)

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

Disease context

Charcot-Marie-Tooth disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Yunis-Varon syndrome Charcot-Marie-Tooth disease type 4J amyotrophic lateral sclerosis type 11 bilateral parasagittal parieto-occipital polymicrogyria 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.2376+2T>G 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

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-val654ala (accessed [today's date]).

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