Is CASP4 p.Asp47Asn (c.139G>A) pathogenic?

CASP4 p.Asp47Asn (c.139G>A) is classified Benign in CASP4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0755); Common (popmax 8.94%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CASP4 p.Asp47Asn (c.139G>A)?

AlphaMissense predicts likely benign (score 0.0755) — an in-silico prediction, not a clinical call.

CASP4 p.Asp47Asn

Q: How common is CASP4 p.Asp47Asn (c.139G>A) in the general population?

CASP4 p.Asp47Asn (c.139G>A) is common (popmax 8.94%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.139G>A · rs56226603 · VCV787097

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0755 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.94%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0755	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.47	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 -2.4	GERP -2.8
Regional constraint	o/e 0.97	unconstrained · MANE · 24 kb · p 0.53 · regional, not allelic
Overall
CADD	0.988	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 8.94% African / African-American · 6,702/74,982 alleles

Filtering AF 8.76% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.69%

Overall 0.486% 7,843/1,613,718 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.94%	11
Admixed American	0.699%	143
Remaining individualsnot grpmax-eligible	0.679%	147
Middle Eastern	0.462%	216
South Asian	0.0209%	4,793
European (non-Finnish)	0.0208%	4,816
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,865
East Asian	0.00669%	14,955

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: CASP4
Protein: p.Asp47Asn
Coding: c.139G>A
MANE Select: NM_001225
dbSNP: rs56226603
Type: single nucleotide variant
Location: chr11:104954870 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.00 · 11 PDB
Residue 47: a UniProt-annotated variant site (in); the card domain; the 'required for lps-binding' region

Full CASP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP4 p.Glu284Asp Benign ★★ same type
CASP4 p.Ala94Val Uncertain significance ★ ⚠ same type
CASP4 p.Arg116Gly Uncertain significance ★ ⚠ same type
CASP4 p.Arg136His Uncertain significance ★ ⚠ same type
CASP4 p.Arg136Ser Uncertain significance ★ ⚠ same type
CASP4 p.Arg259Ile Uncertain significance ★ ⚠ same type
CASP4 p.Arg263Cys Uncertain significance ★ ⚠ same type
CASP4 p.Arg66His 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/casp4-p-asp47asn (accessed [today's date]).

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