Is CSRP2 p.Cys146Arg (c.436T>C) pathogenic?

CSRP2 p.Cys146Arg (c.436T>C) is classified Uncertain significance in CSRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 0.00134%, afr).

How common is CSRP2 p.Cys146Arg (c.436T>C) in the general population?

CSRP2 p.Cys146Arg (c.436T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CSRP2 p.Cys146Arg (c.436T>C)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

CSRP2 p.Cys146Arg

c.436T>C · VCV3497942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · 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	0.9998	likely pathogenic · top 3% in CSRP2
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -14.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	27.0	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 · 1/74,836 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000682% 11/1,612,314 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,338
African / African-Americangrpmax	0.00134%	74,836
South Asian	0.0011%	90,992
European (non-Finnish)	0.000678%	147,472

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: CSRP2
Protein: p.Cys146Arg
Coding: c.436T>C
MANE Select: NM_001321
Type: single nucleotide variant
Location: chr12:76859616 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.07
Residue 146: the lim zinc-binding 2 domain

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

Similar variants

CSRP2 p.Cys146Tyr Uncertain significance ★ ⚠ same residue
CSRP2 p.Arg145Gln Uncertain significance ★ ⚠ same type
CSRP2 p.Arg84His Uncertain significance ★ ⚠ same type
CSRP2 p.Asn81Thr 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
CSRP2 p.Gly183Asp 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-cys146arg (accessed [today's date]).

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