Is CSHL1 p.Pro31Ser (c.91C>T) pathogenic?

CSHL1 p.Pro31Ser (c.91C>T) is classified Uncertain significance in CSHL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: likely benign (0.1369); Ultra-rare (popmax 0.0165%, mid).

How common is CSHL1 p.Pro31Ser (c.91C>T) in the general population?

CSHL1 p.Pro31Ser (c.91C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CSHL1 p.Pro31Ser (c.91C>T)?

AlphaMissense predicts likely benign (score 0.1369) — an in-silico prediction, not a clinical call.

CSHL1 p.Pro31Ser

c.91C>T · VCV4234877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1369	likely benign
REVEL	0.384	indeterminate
SaProt	LLR -8.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP -3.7, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 1,482 bp · p 0.00018 · regional, not allelic
Overall
CADD	16.49	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.84e-05% 1/1,461,884 alleles · ultra-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: CSHL1
Protein: p.Pro31Ser
Coding: c.91C>T
MANE Select: NM_022579
Type: single nucleotide variant
Location: chr17:63910844 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.99

Full CSHL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSHL1 p.Thr127= Benign ★★ same type
CSHL1 p.Thr127Ile Benign ★★ same type
CSHL1 p.Thr129Ala Benign ★★ same type
CSHL1 p.Ala186Thr Uncertain significance ★ ⚠ same type
CSHL1 p.Ala26Val Uncertain significance ★ ⚠ same type
CSHL1 p.Ala46Thr Uncertain significance ★ ⚠ same type
CSHL1 p.Ala65Thr Uncertain significance ★ ⚠ same type
CSHL1 p.Arg117Gln 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/cshl1-p-pro31ser (accessed [today's date]).

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