Is CSMD3 p.Ser3091Pro (c.9271T>C) pathogenic?

CSMD3 p.Ser3091Pro (c.9271T>C) is classified Benign in CSMD3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-14). AlphaMissense: likely benign (0.3106); Common (popmax 12%, amr) — too common for a highly-penetrant pathogenic allele; Associated with CSMD3-related disorder.

What condition is associated with CSMD3 p.Ser3091Pro (c.9271T>C)?

CSMD3 p.Ser3091Pro (c.9271T>C) is associated with CSMD3-related disorder (ClinVar).

What do computational predictors say about CSMD3 p.Ser3091Pro (c.9271T>C)?

AlphaMissense predicts likely benign (score 0.3106) — an in-silico prediction, not a clinical call.

CSMD3 p.Ser3091Pro

Q: How common is CSMD3 p.Ser3091Pro (c.9271T>C) in the general population?

CSMD3 p.Ser3091Pro (c.9271T>C) is common (popmax 12%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.9271T>C · rs145027071 · VCV3061006

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3106 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

CSMD3-related disorder

Computational evidence

Protein change
AlphaMissense	0.3106	likely benign
REVEL	0.504	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 0.49, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 442 kb · p 0.031 · regional, not allelic
Overall
CADD	23.0	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 12% Admixed American · 7,173/59,876 alleles

Filtering AF 11.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.7%

Overall 0.49% 7,915/1,613,740 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	12%	8
Remaining individualsnot grpmax-eligible	0.496%	202
African / African-American	0.164%	610
East Asian	0.143%	701
South Asian	0.106%	939
Finnishnot grpmax-eligible	0.0203%	4,925
Middle Eastern	0.0165%	6,060
European (non-Finnish)	0.0114%	8,805

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: CSMD3
Protein: p.Ser3091Pro
Coding: c.9271T>C
MANE Select: NM_198123
dbSNP: rs145027071
Type: single nucleotide variant
Location: chr8:112287124 (GRCh38)
Gene constraint: LOEUF 0.464 · pLI 0.97 (gnomAD)
Residue 3091: a disulfide bond; the sushi 22 domain

Full CSMD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CSMD3-related disorder

Similar variants

CSMD3 p.Glu2761Val Uncertain significance ★★ same condition
CSMD3 p.Asp211His Uncertain significance ★ ⚠ same condition
CSMD3 c.7165+5G>A Uncertain significance same condition
CSMD3 p.Ala1895Val Uncertain significance ⚠ same condition
CSMD3 p.Asn1264Tyr Uncertain significance same condition
CSMD3 p.Asn2918Thr Uncertain significance same condition
CSMD3 p.Glu1266Ala Uncertain significance same condition
CSMD3 p.Met2992Ile Uncertain significance same condition

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/csmd3-p-ser3091pro (accessed [today's date]).

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