Is CSMD1 p.Pro3469Ala (c.10405C>G) pathogenic?

CSMD1 p.Pro3469Ala (c.10405C>G) is classified Benign in CSMD1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-04-20). AlphaMissense: likely benign (0.0664); Low-frequency (popmax 2.23%, sas); Associated with CSMD1-related disorder.

What condition is associated with CSMD1 p.Pro3469Ala (c.10405C>G)?

CSMD1 p.Pro3469Ala (c.10405C>G) is associated with CSMD1-related disorder (ClinVar).

How common is CSMD1 p.Pro3469Ala (c.10405C>G) in the general population?

CSMD1 p.Pro3469Ala (c.10405C>G) is low-frequency (popmax 2.23%, sas) (gnomAD).

What do computational predictors say about CSMD1 p.Pro3469Ala (c.10405C>G)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

CSMD1 p.Pro3469Ala

c.10405C>G · rs375524577 · VCV3045826

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.23%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

CSMD1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.037	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.011, phastCons 1
Regional constraint	o/e 1.53	unconstrained · MANE · 2,056 kb · p 5.8e-277 · regional, not allelic
Overall
CADD	6.396	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 2.23% South Asian · 1,903/85,450 alleles

Filtering AF 2.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.11%

Overall 0.13% 2,034/1,567,484 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2.23%	45
Remaining individualsnot grpmax-eligible	0.171%	585
Middle Eastern	0.117%	852
Admixed American	0.0115%	8,669
African / African-American	0.00679%	14,724
European (non-Finnish)	0.000779%	128,366

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: CSMD1
Protein: p.Pro3469Ala
Coding: c.10405C>G
MANE Select: NM_033225
dbSNP: rs375524577
Type: single nucleotide variant
Location: chr8:2942602 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)

Full CSMD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CSMD1-related disorder

Similar variants

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CSMD1 p.Lys1718Asn Uncertain significance ★★ ⚠ same condition
CSMD1 p.Ser319Ter Pathogenic ★ same condition
CSMD1 c.10314+1G>A Uncertain significance ★ same condition
CSMD1 c.1344+31812G>A Uncertain significance ★ same condition
CSMD1 p.Ala1706Gly 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/csmd1-p-pro3469ala (accessed [today's date]).

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