Is CASP7 p.Pro289Ser (c.865C>T) pathogenic?

CASP7 p.Pro289Ser (c.865C>T) is classified Uncertain significance in CASP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-16). AlphaMissense: likely pathogenic (0.9162); Very rare (popmax 0.000169%, nfe).

How common is CASP7 p.Pro289Ser (c.865C>T) in the general population?

CASP7 p.Pro289Ser (c.865C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CASP7 p.Pro289Ser (c.865C>T)?

AlphaMissense predicts likely pathogenic (score 0.9162) — an in-silico prediction, not a clinical call.

CASP7 p.Pro289Ser

c.865C>T · rs1853480485 · VCV2526028

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9162 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9162	likely pathogenic
REVEL	0.792	moderately pathogenic-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 32 kb · p 0.049 · regional, not allelic
Overall
CADD	26.1	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 0.000169% European (non-Finnish) · 2/1,180,020 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,886 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: CASP7
Protein: p.Pro289Ser
Coding: c.865C>T
MANE Select: NM_001227
dbSNP: rs1853480485
Type: single nucleotide variant
Location: chr10:113729493 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.05 · 47 PDB

Full CASP7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP7 p.Pro289Thr Uncertain significance ★ ⚠ same residue
CASP7 p.Pro289= Likely benign ★ same residue
CASP7 p.Asp255Glu Benign ★★ same type
CASP7 p.Ala164Val Uncertain significance ★ ⚠ same type
CASP7 p.Ala270Ser Uncertain significance ★ ⚠ same type
CASP7 p.Ala270Val Uncertain significance ★ ⚠ same type
CASP7 p.Arg210Gln Uncertain significance ★ ⚠ same type
CASP7 p.Arg28Gln 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/casp7-p-pro289ser (accessed [today's date]).

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