Is CRIP2 p.Ser74Phe (c.221C>T) pathogenic?

CRIP2 p.Ser74Phe (c.221C>T) is classified Uncertain significance in CRIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely pathogenic (0.8928); Very rare (popmax 0.00511%, eas).

How common is CRIP2 p.Ser74Phe (c.221C>T) in the general population?

CRIP2 p.Ser74Phe (c.221C>T) is very rare (popmax 0.00511%, eas) (gnomAD).

What do computational predictors say about CRIP2 p.Ser74Phe (c.221C>T)?

AlphaMissense predicts likely pathogenic (score 0.8928) — an in-silico prediction, not a clinical call.

CRIP2 p.Ser74Phe

c.221C>T · rs1555436504 · VCV2252524

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8928 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00511%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8928	likely pathogenic
REVEL	0.62	indeterminate
SaProt	LLR -13.19	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 4.6	GERP 0.012, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 4,787 bp · p 4.9e-07 · 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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00511% East Asian · 2/39,114 alleles

Filtering AF 0.000862% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000698%

Overall 0.00147% 21/1,432,222 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00511%	19,557
Finnishnot grpmax-eligible	0.00241%	41,568
Remaining individualsnot grpmax-eligible	0.00181%	55,204
South Asian	0.00148%	67,406
European (non-Finnish)	0.00146%	68,660

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.Ser74Phe
Coding: c.221C>T
MANE Select: NM_001312
dbSNP: rs1555436504
Type: single nucleotide variant
Location: chr14:105478755 (GRCh38)
Gene constraint: LOEUF 1.553 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.78 · 1 PDB

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-ser74phe (accessed [today's date]).

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