Is FES p.Arg154His (c.461G>A) pathogenic?

FES p.Arg154His (c.461G>A) is classified Uncertain significance in FES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-14). AlphaMissense: likely benign (0.2448); Ultra-rare (popmax 0.011%, nfe).

How common is FES p.Arg154His (c.461G>A) in the general population?

FES p.Arg154His (c.461G>A) is ultra-rare (popmax 0.011%, nfe) (gnomAD).

What do computational predictors say about FES p.Arg154His (c.461G>A)?

AlphaMissense predicts likely benign (score 0.2448) — an in-silico prediction, not a clinical call.

FES p.Arg154His

c.461G>A · rs372642630 · VCV2223662

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2448 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2448	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.65, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 9.3e-05 · regional, not allelic
Overall
CADD	33.0	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 0.011% European (non-Finnish) · 130/1,180,042 alleles

Filtering AF 0.00944% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00892% 144/1,614,046 alleles · ultra-rare exomes 135/1,461,772 · genomes 9/152,274 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.011%	9,077
African / African-American	0.008%	12,493
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Finnishnot grpmax-eligible	0.00313%	31,977
Admixed American	0.00167%	60,006
South Asian	0.0011%	91,088

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.Arg154His
Coding: c.461G>A
MANE Select: NM_002005
dbSNP: rs372642630
Type: single nucleotide variant
Location: chr15:90887034 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.63 · 12 PDB
Residue 154: 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.Ala243Val Uncertain significance ★ ⚠ same type
FES p.Ala370Val Uncertain significance ★ ⚠ same type
FES p.Ala45Pro 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-arg154his (accessed [today's date]).

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