Is CRPPA p.Ala451Ser (c.1351G>T) pathogenic?

CRPPA p.Ala451Ser (c.1351G>T) is classified Uncertain significance in CRPPA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.1589); Very rare (popmax 0.00205%, amr).

How common is CRPPA p.Ala451Ser (c.1351G>T) in the general population?

CRPPA p.Ala451Ser (c.1351G>T) is very rare (popmax 0.00205%, amr) (gnomAD).

What do computational predictors say about CRPPA p.Ala451Ser (c.1351G>T)?

AlphaMissense predicts likely benign (score 0.1589) — an in-silico prediction, not a clinical call.

CRPPA p.Ala451Ser

c.1351G>T · VCV3269610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1589 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00205%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1589	likely benign
REVEL	0.413	indeterminate
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 330 kb · p 0.001 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00205% Admixed American · 1/48,802 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000866%

Overall 0.00131% 20/1,530,276 alleles · very rare exomes 18/1,378,146 · genomes 2/152,130 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00205%	48,802
European (non-Finnish)	0.00168%	59,503

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.Ala451Ser
Coding: c.1351G>T
MANE Select: NM_001101426
Type: single nucleotide variant
Location: chr7:16091700 (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 451: a UniProt-annotated variant site (in mddgc7; atypical form presenting with congenital muscular dystrophy); a UniProt-annotated variant site (in mddgc7)

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

Similar variants

CRPPA p.Ala451Gly 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
CRPPA p.Gln215Ter Pathogenic/Likely 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-ala451ser (accessed [today's date]).

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