Is CSRP2 p.Tyr166His (c.496T>C) pathogenic?

CSRP2 p.Tyr166His (c.496T>C) is classified Uncertain significance in CSRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely pathogenic (0.9325); Very rare (popmax 0.00134%, afr).

How common is CSRP2 p.Tyr166His (c.496T>C) in the general population?

CSRP2 p.Tyr166His (c.496T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CSRP2 p.Tyr166His (c.496T>C)?

AlphaMissense predicts likely pathogenic (score 0.9325) — an in-silico prediction, not a clinical call.

CSRP2 p.Tyr166His

c.496T>C · VCV4007717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9325 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9325	likely pathogenic
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -10.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,305 bp · p 0.11 · regional, not allelic
Overall
CADD	26.4	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,830 alleles

Overall 0.000658% 1/152,074 alleles · very rare

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: CSRP2
Protein: p.Tyr166His
Coding: c.496T>C
MANE Select: NM_001321
Type: single nucleotide variant
Location: chr12:76859556 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.07
Residue 166: the lim zinc-binding 2 domain

Full CSRP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSRP2 p.Arg145Gln Uncertain significance ★ ⚠ same type
CSRP2 p.Arg84His Uncertain significance ★ ⚠ same type
CSRP2 p.Asn81Thr Uncertain significance ★ ⚠ same type
CSRP2 p.Cys146Arg Uncertain significance ★ ⚠ same type
CSRP2 p.Cys146Tyr Uncertain significance ★ ⚠ same type
CSRP2 p.Glu117Asp Uncertain significance ★ ⚠ same type
CSRP2 p.Glu130Lys Uncertain significance ★ ⚠ same type
CSRP2 p.Glu54Lys 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/csrp2-p-tyr166his (accessed [today's date]).

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