Is FES p.Pro397Arg (c.1190C>G) pathogenic?

FES p.Pro397Arg (c.1190C>G) is classified Uncertain significance in FES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: likely benign (0.1377); Rare (popmax 0.195%, nfe).

How common is FES p.Pro397Arg (c.1190C>G) in the general population?

FES p.Pro397Arg (c.1190C>G) is rare (popmax 0.195%, nfe) (gnomAD).

What do computational predictors say about FES p.Pro397Arg (c.1190C>G)?

AlphaMissense predicts likely benign (score 0.1377) — an in-silico prediction, not a clinical call.

FES p.Pro397Arg

c.1190C>G · VCV4668275

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1377 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.195%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1377	likely benign
REVEL	0.44	indeterminate
SaProt	LLR -8.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.87, phastCons 0.98
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 9.3e-05 · regional, not allelic
Overall
CADD	19.28	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 0.195% European (non-Finnish) · 2,295/1,178,400 alleles

Filtering AF 0.188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.185%

Overall 0.156% 2,494/1,599,974 alleles · rare exomes 2,323/1,447,756 · genomes 171/152,218 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.195%	513
Remaining individualsnot grpmax-eligible	0.155%	647
Admixed American	0.0685%	1,460
Ashkenazi Jewishnot grpmax-eligible	0.0373%	2,678
Finnishnot grpmax-eligible	0.0358%	2,797
African / African-American	0.0307%	3,259
Middle Eastern	0.0183%	5,468
East Asian	0.0156%	6,398
South Asian	0.0011%	90,874

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.Pro397Arg
Coding: c.1190C>G
MANE Select: NM_002005
Type: single nucleotide variant
Location: chr15:90890232 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.63 · 12 PDB
Residue 397: the 'disordered' region

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

Similar variants

FES p.Pro397Leu Uncertain significance ★ ⚠ same residue
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

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-pro397arg (accessed [today's date]).

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