Is ESRP2 p.Arg351Trp (c.1051C>T) pathogenic?

ESRP2 p.Arg351Trp (c.1051C>T) is classified Uncertain significance in ESRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely pathogenic (0.9695); Ultra-rare (popmax 0.015%, amr).

How common is ESRP2 p.Arg351Trp (c.1051C>T) in the general population?

ESRP2 p.Arg351Trp (c.1051C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about ESRP2 p.Arg351Trp (c.1051C>T)?

AlphaMissense predicts likely pathogenic (score 0.9695) — an in-silico prediction, not a clinical call.

ESRP2 p.Arg351Trp

c.1051C>T · VCV3510427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9695	likely pathogenic
REVEL	0.433	indeterminate
SaProt	LLR -14.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 5,816 bp · p 0.00093 · regional, not allelic
Overall
CADD	23.9	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R361W vs ClinVar R351W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/59,982 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00452% 73/1,613,826 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,665
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00458%	21,851
African / African-American	0.00401%	24,963
East Asian	0.00223%	44,880
South Asian	0.0011%	91,060

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: ESRP2
Protein: p.Arg351Trp
Coding: c.1051C>T
MANE Select: NM_024939
Type: single nucleotide variant
Location: chr16:68232050 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.87
Residue 351: the rrm 1 domain

Full ESRP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESRP2 p.Arg351Gln Uncertain significance ★ ⚠ same residue
ESRP2 p.Gly122Arg Uncertain significance ★★ ⚠ same type
ESRP2 p.Gly463Glu Uncertain significance ★★ ⚠ same type
ESRP2 p.Leu681Phe Uncertain significance ★★ ⚠ same type
ESRP2 p.Ala691Thr Benign ★★ same type
ESRP2 p.Thr475= Benign ★★ same type
ESRP2 p.Ala20Pro Uncertain significance ★ ⚠ same type
ESRP2 p.Ala273Val 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/esrp2-p-arg351trp (accessed [today's date]).

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