Is CSMD2 p.Arg1110His (c.3329G>A) pathogenic?

CSMD2 p.Arg1110His (c.3329G>A) is classified Uncertain significance in CSMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.1902); Ultra-rare (popmax 0.0156%, eas).

How common is CSMD2 p.Arg1110His (c.3329G>A) in the general population?

CSMD2 p.Arg1110His (c.3329G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about CSMD2 p.Arg1110His (c.3329G>A)?

AlphaMissense predicts likely benign (score 0.1902) — an in-silico prediction, not a clinical call.

CSMD2 p.Arg1110His

c.3329G>A · VCV3497687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1902 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Computational evidence

Protein change
AlphaMissense	0.1902	likely benign
REVEL	0.637	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 331 kb · p 5.5e-29 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1070H vs ClinVar R1110H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,880 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.0039% 63/1,613,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,411
Remaining individualsnot grpmax-eligible	0.0048%	20,836
African / African-American	0.004%	25,022
European (non-Finnish)	0.00398%	25,107
Admixed American	0.00333%	30,017
South Asian	0.0011%	91,086

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: CSMD2
Protein: p.Arg1110His
Coding: c.3329G>A
MANE Select: NM_001281956
Type: single nucleotide variant
Location: chr1:33714664 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Residue 1110: the cub 7 domain; a disulfide bond

Full CSMD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSMD2 p.Pro1506= Likely benign ★★ same type
CSMD2 p.Ser3015= Benign ★★ same type
CSMD2 c.404+2T>A Uncertain significance ★ same type
CSMD2 c.6344-398G>T Uncertain significance ★ same type
CSMD2 c.6344-422A>G Uncertain significance ★ same type
CSMD2 c.6344-423T>C Uncertain significance ★ same type
CSMD2 c.6344-429G>A Uncertain significance ★ same type
CSMD2 c.6344-435G>A 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/csmd2-p-arg1110his (accessed [today's date]).

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