Is CASP2 p.Gln331Glu (c.991C>G) pathogenic?

CASP2 p.Gln331Glu (c.991C>G) is classified Uncertain significance in CASP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-10). AlphaMissense: likely benign (0.1085); Ultra-rare (popmax 0.0165%, sas).

How common is CASP2 p.Gln331Glu (c.991C>G) in the general population?

CASP2 p.Gln331Glu (c.991C>G) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

What do computational predictors say about CASP2 p.Gln331Glu (c.991C>G)?

AlphaMissense predicts likely benign (score 0.1085) — an in-silico prediction, not a clinical call.

CASP2 p.Gln331Glu

c.991C>G · rs771213829 · VCV2219015

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1085	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -5.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 3.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 13 kb · p 0.00043 · regional, not allelic
Overall
CADD	22.3	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 0.0165% South Asian · 15/91,052 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00756% 122/1,613,616 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,070
European (non-Finnish)	0.00865%	11,567
Remaining individualsnot grpmax-eligible	0.0032%	31,236
African / African-American	0.00267%	37,404
Admixed American	0.00167%	59,954

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: CASP2
Protein: p.Gln331Glu
Coding: c.991C>G
MANE Select: NM_032982
dbSNP: rs771213829
Type: single nucleotide variant
Location: chr7:143303807 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.95 · 17 PDB
Residue 331: a UniProt-annotated variant site (in mrt80; likely pathogenic); the 'disordered' region

Full CASP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP2 p.Ala412= Likely benign ★★ same type
CASP2 p.Gly7= Likely benign ★★ same type
CASP2 p.Ile387= Benign/Likely benign ★★ same type
CASP2 p.Lys254= Benign/Likely benign ★★ same type
CASP2 p.Thr267= Benign/Likely benign ★★ same type
CASP2 p.Tyr151= Benign ★★ same type
CASP2 p.Val29= Benign ★★ same type
CASP2 c.876+1G>T 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/casp2-p-gln331glu (accessed [today's date]).

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