Is FIG4 p.His537Pro (c.1610A>C) pathogenic?

FIG4 p.His537Pro (c.1610A>C) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). AlphaMissense: likely pathogenic (0.9977); Absent from gnomAD v4.1.

How common is FIG4 p.His537Pro (c.1610A>C) in the general population?

FIG4 p.His537Pro (c.1610A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FIG4 p.His537Pro (c.1610A>C)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

FIG4 p.His537Pro

c.1610A>C · rs2486185556 · VCV1806994

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic · top 7% in FIG4
REVEL	0.527	indeterminate
SaProt	LLR -16.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 34 kb · p 8.8e-09 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FIG4
Protein: p.His537Pro
Coding: c.1610A>C
MANE Select: NM_014845
dbSNP: rs2486185556
Type: single nucleotide variant
Location: chr6:109766755 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB
Residue 537: the sac domain

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

Similar variants

FIG4 c.1040-1G>A Likely pathogenic ★★ same type
FIG4 c.1584-1G>T Likely pathogenic ★★ same type
FIG4 c.1948+1G>A Likely pathogenic ★★ same type
FIG4 c.1949-10T>G Pathogenic/Likely pathogenic ★★ same type
FIG4 c.2376+2T>G Likely pathogenic ★★ same type
FIG4 c.2459+1G>A Pathogenic ★★ same type
FIG4 c.877-2A>C Pathogenic/Likely pathogenic ★★ same type
FIG4 p.Arg152Ter Pathogenic/Likely pathogenic ★★ same type

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-his537pro (accessed [today's date]).

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