Is FIG4 p.Pro185Thr (c.553C>A) pathogenic?

FIG4 p.Pro185Thr (c.553C>A) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-26). AlphaMissense: likely benign (0.3358); Very rare (popmax 0.000124%); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with FIG4 p.Pro185Thr (c.553C>A)?

FIG4 p.Pro185Thr (c.553C>A) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is FIG4 p.Pro185Thr (c.553C>A) in the general population?

FIG4 p.Pro185Thr (c.553C>A) is very rare (popmax 0.000124%) (gnomAD).

What do computational predictors say about FIG4 p.Pro185Thr (c.553C>A)?

AlphaMissense predicts likely benign (score 0.3358) — an in-silico prediction, not a clinical call.

FIG4 p.Pro185Thr

c.553C>A · rs1317532051 · VCV2117702

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3358 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.3358	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -10.16	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.42 · regional, not allelic
Overall
CADD	21.4	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 0.000124%

Overall 0.000124% 2/1,612,130 alleles · very rare exomes 1/1,460,046 · genomes 1/152,084 · joint denominator

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.Pro185Thr
Coding: c.553C>A
MANE Select: NM_014845
dbSNP: rs1317532051
Type: single nucleotide variant
Location: chr6:109735205 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 185: the sac domain

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

Disease context

Charcot-Marie-Tooth disease type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-pro185thr (accessed [today's date]).

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