Is CRIP2 p.Tyr58His (c.172T>C) pathogenic?

CRIP2 p.Tyr58His (c.172T>C) is classified Uncertain significance in CRIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.9404); Very rare (popmax 0.00334%, amr).

How common is CRIP2 p.Tyr58His (c.172T>C) in the general population?

CRIP2 p.Tyr58His (c.172T>C) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about CRIP2 p.Tyr58His (c.172T>C)?

AlphaMissense predicts likely pathogenic (score 0.9404) — an in-silico prediction, not a clinical call.

CRIP2 p.Tyr58His

c.172T>C · VCV4656616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9404 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9404	likely pathogenic
REVEL	0.479	indeterminate
SaProt	LLR -10.71	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 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 4,787 bp · p 4.9e-07 · regional, not allelic
Overall
CADD	29.9	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,894 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000206% 3/1,456,812 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,947
European (non-Finnish)	8.48e-05%	1,179,106

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: CRIP2
Protein: p.Tyr58His
Coding: c.172T>C
MANE Select: NM_001312
Type: single nucleotide variant
Location: chr14:105478483 (GRCh38)
Gene constraint: LOEUF 1.553 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.78 · 1 PDB
Residue 58: an α-helix

Full CRIP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRIP2 p.Ala113Val Uncertain significance ★ ⚠ same type
CRIP2 p.Ala166Thr Uncertain significance ★ ⚠ same type
CRIP2 p.Ala82Thr Uncertain significance ★ ⚠ same type
CRIP2 p.Ala96Gly Uncertain significance ★ ⚠ same type
CRIP2 p.Ala98Thr Uncertain significance ★ ⚠ same type
CRIP2 p.Arg128His Uncertain significance ★ ⚠ same type
CRIP2 p.Arg148Gly Uncertain significance ★ ⚠ same type
CRIP2 p.Arg148Trp 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/crip2-p-tyr58his (accessed [today's date]).

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