Is CASP4 p.Arg136His (c.407G>A) pathogenic?

CASP4 p.Arg136His (c.407G>A) is classified Uncertain significance in CASP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-15). AlphaMissense: ambiguous (0.4472); Ultra-rare (popmax 0.0248%, nfe).

How common is CASP4 p.Arg136His (c.407G>A) in the general population?

CASP4 p.Arg136His (c.407G>A) is ultra-rare (popmax 0.0248%, nfe) (gnomAD).

What do computational predictors say about CASP4 p.Arg136His (c.407G>A)?

AlphaMissense predicts ambiguous (score 0.4472) — an in-silico prediction, not a clinical call.

CASP4 p.Arg136His

c.407G>A · rs139811045 · VCV2360536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4472 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0248%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4472	ambiguous
REVEL	0.404	indeterminate
SaProt	LLR -13.89	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.97, phastCons 0.067
Regional constraint	o/e 0.97	unconstrained · MANE · 24 kb · p 0.53 · regional, not allelic
Overall
CADD	23.4	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 0.0248% European (non-Finnish) · 292/1,179,438 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0215%

Overall 0.0211% 340/1,613,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0368%	2,715
European (non-Finnish)grpmax	0.0248%	4,039
East Asian	0.0201%	4,987
South Asian	0.0143%	7,005
African / African-American	0.00401%	24,939

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg136His
Coding: c.407G>A
MANE Select: NM_001225
dbSNP: rs139811045
Type: single nucleotide variant
Location: chr11:104951064 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.00 · 11 PDB
Residue 136: a β-strand

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

Similar variants

CASP4 p.Arg136Ser Uncertain significance ★ ⚠ same residue
CASP4 p.Asp47Asn Benign ★★ same type
CASP4 p.Glu284Asp Benign ★★ same type
CASP4 p.Ala94Val Uncertain significance ★ ⚠ same type
CASP4 p.Arg116Gly 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-arg136his (accessed [today's date]).

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