Is CRPPA p.Pro214Ser (c.640C>T) pathogenic?

CRPPA p.Pro214Ser (c.640C>T) is classified Uncertain significance in CRPPA (ClinVar, Single submitter, 1 submitter; last evaluated 2016-02-01). AlphaMissense: likely pathogenic (0.987); Very rare (popmax 0.00133%, afr).

How common is CRPPA p.Pro214Ser (c.640C>T) in the general population?

CRPPA p.Pro214Ser (c.640C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CRPPA p.Pro214Ser (c.640C>T)?

AlphaMissense predicts likely pathogenic (score 0.987) — an in-silico prediction, not a clinical call.

CRPPA p.Pro214Ser

c.640C>T · rs886043226 · VCV285826

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.987	likely pathogenic · top 1% in CRPPA
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -9.85	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 6.1, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 330 kb · p 0.001 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,980 alleles

Overall 6.85e-05% 1/1,459,460 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: CRPPA
Protein: p.Pro214Ser
Coding: c.640C>T
MANE Select: NM_001101426
dbSNP: rs886043226
Type: single nucleotide variant
Location: chr7:16376136 (GRCh38)
Gene constraint: LOEUF 1.462 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.63 · 1 PDB
Residue 214: a β-strand

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

Similar variants

CRPPA p.Pro214Leu Uncertain significance ★★ ⚠ same residue
CRPPA p.Pro214Thr Uncertain significance ★★ ⚠ same residue
CRPPA c.1120-1G>T Pathogenic ★★ same type
CRPPA c.258-1G>C Pathogenic/Likely pathogenic ★★ same type
CRPPA c.835+2T>C Pathogenic/Likely pathogenic ★★ same type
CRPPA p.Arg184Ter Pathogenic ★★ same type
CRPPA p.Arg205Cys Likely pathogenic ★★ same type
CRPPA p.Arg268Ter Pathogenic ★★ 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/crppa-p-pro214ser (accessed [today's date]).

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