Is FES p.Ala243Val (c.728C>T) pathogenic?

FES p.Ala243Val (c.728C>T) is classified Uncertain significance in FES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-28). AlphaMissense: likely benign (0.0913); Very rare (popmax 0.00966%, nfe).

How common is FES p.Ala243Val (c.728C>T) in the general population?

FES p.Ala243Val (c.728C>T) is very rare (popmax 0.00966%, nfe) (gnomAD).

What do computational predictors say about FES p.Ala243Val (c.728C>T)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

FES p.Ala243Val

c.728C>T · VCV3849961

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00966%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -8.24	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 3.3	GERP 1.9, phastCons 0.71
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 9.3e-05 · regional, not allelic
Overall
CADD	21.2	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 0.00966% European (non-Finnish) · 114/1,180,022 alleles

Filtering AF 0.00817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00761%

Overall 0.00731% 118/1,614,034 alleles · very rare exomes 110/1,461,764 · genomes 8/152,270 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00966%	10,351
East Asian	0.00446%	22,428
Remaining individualsnot grpmax-eligible	0.0016%	62,510
African / African-American	0.00133%	75,046

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: FES
Protein: p.Ala243Val
Coding: c.728C>T
MANE Select: NM_002005
Type: single nucleotide variant
Location: chr15:90889365 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.63 · 12 PDB
Residue 243: 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.Ala192Pro Uncertain significance ★ ⚠ same type
FES p.Ala22Asp 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-ala243val (accessed [today's date]).

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