Is CSH2 p.Pro87Ser (c.259C>T) pathogenic?

CSH2 p.Pro87Ser (c.259C>T) is classified Uncertain significance in CSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-23). AlphaMissense: likely pathogenic (0.6156); Ultra-rare (popmax 0.0222%, amr).

How common is CSH2 p.Pro87Ser (c.259C>T) in the general population?

CSH2 p.Pro87Ser (c.259C>T) is ultra-rare (popmax 0.0222%, amr) (gnomAD).

What do computational predictors say about CSH2 p.Pro87Ser (c.259C>T)?

AlphaMissense predicts likely pathogenic (score 0.6156) — an in-silico prediction, not a clinical call.

CSH2 p.Pro87Ser

c.259C>T · rs1219707292 · VCV2411864

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6156 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0222%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6156	likely pathogenic · top 10% in CSH2
REVEL	0.477	indeterminate
SaProt	LLR -5.28	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.14	constrained · MANE · 880 bp · p 6.3e-20 · regional, not allelic
Overall
CADD	23.8	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 0.0222% Admixed American · 7/31,514 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00729%

Overall 0.00222% 23/1,035,318 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0222%	4,502
Remaining individualsnot grpmax-eligible	0.00231%	43,316
European (non-Finnish)	0.00199%	50,192

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: CSH2
Protein: p.Pro87Ser
Coding: c.259C>T
MANE Select: NM_020991
dbSNP: rs1219707292
Type: single nucleotide variant
Location: chr17:63872867 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.15
Residue 87: a disulfide bond

Full CSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSH2 p.Ter218Gln Benign ★★ same type
CSH2 p.Ala39Thr Uncertain significance ★ ⚠ same type
CSH2 p.Ala46Val Uncertain significance ★ ⚠ same type
CSH2 p.Arg103Cys Uncertain significance ★ ⚠ same type
CSH2 p.Arg117Trp Uncertain significance ★ ⚠ same type
CSH2 p.Arg159Cys Uncertain significance ★ ⚠ same type
CSH2 p.Arg160Gln Uncertain significance ★ ⚠ same type
CSH2 p.Arg160Trp 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/csh2-p-pro87ser (accessed [today's date]).

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