Is CASP4 p.Ser199Pro (c.595T>C) pathogenic?

CASP4 p.Ser199Pro (c.595T>C) is classified Uncertain significance in CASP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: ambiguous (0.4183); Very rare (popmax 0.000254%, nfe).

How common is CASP4 p.Ser199Pro (c.595T>C) in the general population?

CASP4 p.Ser199Pro (c.595T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CASP4 p.Ser199Pro (c.595T>C)?

AlphaMissense predicts ambiguous (score 0.4183) — an in-silico prediction, not a clinical call.

CASP4 p.Ser199Pro

c.595T>C · VCV3995618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4183	ambiguous
REVEL	0.113	moderately benign-leaning
SaProt	LLR -13.20	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.35	GERP -3.7
Regional constraint	o/e 0.97	unconstrained · MANE · 24 kb · p 0.53 · regional, not allelic
Overall
CADD	18.55	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 0.000254% European (non-Finnish) · 3/1,179,906 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,774 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: CASP4
Protein: p.Ser199Pro
Coding: c.595T>C
MANE Select: NM_001225
Type: single nucleotide variant
Location: chr11:104949729 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.00 · 11 PDB

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

Similar variants

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.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

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-ser199pro (accessed [today's date]).

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