Is ESRP2 p.Arg351Gln (c.1052G>A) pathogenic?

ESRP2 p.Arg351Gln (c.1052G>A) is classified Uncertain significance in ESRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely pathogenic (0.9723); Ultra-rare (popmax 0.0103%, nfe).

How common is ESRP2 p.Arg351Gln (c.1052G>A) in the general population?

ESRP2 p.Arg351Gln (c.1052G>A) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about ESRP2 p.Arg351Gln (c.1052G>A)?

AlphaMissense predicts likely pathogenic (score 0.9723) — an in-silico prediction, not a clinical call.

ESRP2 p.Arg351Gln

c.1052G>A · rs186017472 · VCV2355736

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9723 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9723	likely pathogenic
REVEL	0.454	indeterminate
SaProt	LLR -14.28	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 7.7	phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 5,816 bp · p 0.00093 · regional, not allelic
Overall
CADD	28.7	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 R361Q vs ClinVar R351Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0103% European (non-Finnish) · 122/1,179,968 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00828%

Overall 0.00855% 138/1,613,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,683
European (non-Finnish)grpmax	0.0103%	9,672
African / African-American	0.004%	25,001
Admixed American	0.00333%	29,999

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg351Gln
Coding: c.1052G>A
MANE Select: NM_024939
dbSNP: rs186017472
Type: single nucleotide variant
Location: chr16:68232049 (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.Arg351Trp 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-arg351gln (accessed [today's date]).

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