Is CSMD1 p.Asp1237His (c.3709G>C) pathogenic?

CSMD1 p.Asp1237His (c.3709G>C) is classified Uncertain significance in CSMD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: likely benign (0.2448); Ultra-rare (popmax 0.0183%, amr).

How common is CSMD1 p.Asp1237His (c.3709G>C) in the general population?

CSMD1 p.Asp1237His (c.3709G>C) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about CSMD1 p.Asp1237His (c.3709G>C)?

AlphaMissense predicts likely benign (score 0.2448) — an in-silico prediction, not a clinical call.

CSMD1 p.Asp1237His

c.3709G>C · rs373923214 · VCV3078096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2448 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Computational evidence

Protein change
AlphaMissense	0.2448	likely benign
REVEL	0.341	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.53	unconstrained · MANE · 2,056 kb · p 5.8e-277 · regional, not allelic
Overall
CADD	24.8	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 0.0183% Admixed American · 11/59,996 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.0031% 50/1,613,682 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,454
European (non-Finnish)	0.00322%	31,048
African / African-American	0.00133%	74,914

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.Asp1237His
Coding: c.3709G>C
MANE Select: NM_033225
dbSNP: rs373923214
Type: single nucleotide variant
Location: chr8:3308426 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Residue 1237: a disulfide bond; the sushi 7 domain

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

Similar variants

CSMD1 p.Asp1237Asn Uncertain significance ★ ⚠ same residue
CSMD1 p.Ala1296Val Uncertain significance ★★ ⚠ same type
CSMD1 p.Asp908Ala Uncertain significance ★★ ⚠ same type
CSMD1 p.Asp927Asn Uncertain significance ★★ ⚠ same type
CSMD1 p.Gln308Leu Uncertain significance ★★ ⚠ same type
CSMD1 p.Glu1276Asp Uncertain significance ★★ ⚠ same type
CSMD1 p.Gly3156Arg Uncertain significance ★★ ⚠ same type
CSMD1 p.Ile1833Thr 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/csmd1-p-asp1237his (accessed [today's date]).

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