Is FES p.Ala192Pro (c.574G>C) pathogenic?

FES p.Ala192Pro (c.574G>C) is classified Uncertain significance in FES (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-13). AlphaMissense: likely pathogenic (0.9844); Absent from gnomAD v4.1.

How common is FES p.Ala192Pro (c.574G>C) in the general population?

FES p.Ala192Pro (c.574G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FES p.Ala192Pro (c.574G>C)?

AlphaMissense predicts likely pathogenic (score 0.9844) — an in-silico prediction, not a clinical call.

FES p.Ala192Pro

c.574G>C · rs1248269225 · VCV3094493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9844 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9844	likely pathogenic · top 9% in FES
REVEL	0.192	benign-leaning
SaProt	LLR -12.96	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 9.3e-05 · regional, not allelic
Overall
CADD	28.4	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

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: FES
Protein: p.Ala192Pro
Coding: c.574G>C
MANE Select: NM_002005
dbSNP: rs1248269225
Type: single nucleotide variant
Location: chr15:90887276 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.63 · 12 PDB
Residue 192: the f-bar domain; the 'important for interaction with membranes containing phosphoinositides' region; an α-helix

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

Similar variants

FES p.Ala588= Benign ★★ same type
FES p.Leu459= Benign ★★ same type
FES p.Met323Val Benign ★★ same type
FES p.Ala22Asp Uncertain significance ★ ⚠ same type
FES p.Ala243Val Uncertain significance ★ ⚠ same type
FES p.Ala370Val Uncertain significance ★ ⚠ same type
FES p.Ala45Pro Uncertain significance ★ ⚠ same type
FES p.Ala548Pro Uncertain significance ★ ⚠ 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/fes-p-ala192pro (accessed [today's date]).

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