Is CSMD3 p.Arg3025His (c.9074G>A) pathogenic?

CSMD3 p.Arg3025His (c.9074G>A) is classified Uncertain significance in CSMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: likely benign (0.1136); Ultra-rare (popmax 0.0513%, eas).

How common is CSMD3 p.Arg3025His (c.9074G>A) in the general population?

CSMD3 p.Arg3025His (c.9074G>A) is ultra-rare (popmax 0.0513%, eas) (gnomAD).

What do computational predictors say about CSMD3 p.Arg3025His (c.9074G>A)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

CSMD3 p.Arg3025His

c.9074G>A · rs199604170 · VCV3078249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0513%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.262	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.1	GERP 1.1, phastCons 0.52
Regional constraint	o/e 0.96	unconstrained · MANE · 442 kb · p 0.031 · regional, not allelic
Overall
CADD	24.5	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 0.0513% East Asian · 23/44,864 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.00366% 59/1,613,302 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0513%	1,951
Middle Eastern	0.0165%	6,058
Admixed American	0.00835%	11,973
Remaining individualsnot grpmax-eligible	0.00801%	12,491
South Asian	0.00659%	15,179
African / African-American	0.00267%	37,494
Finnishnot grpmax-eligible	0.00156%	64,008
European (non-Finnish)	0.00136%	73,719

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.Arg3025His
Coding: c.9074G>A
MANE Select: NM_198123
dbSNP: rs199604170
Type: single nucleotide variant
Location: chr8:112289439 (GRCh38)
Gene constraint: LOEUF 0.464 · pLI 0.97 (gnomAD)
Residue 3025: a disulfide bond; the sushi 21 domain

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

Similar variants

CSMD3 p.Glu2761Val Uncertain significance ★★ same type
CSMD3 p.Leu3027Phe Uncertain significance ★★ same type
CSMD3 c.4896-3C>T Benign ★★ same type
CSMD3 p.Arg1020His Benign ★★ same type
CSMD3 p.Arg1228Gln Likely benign ★★ same type
CSMD3 p.Arg687= Benign/Likely benign ★★ same type
CSMD3 p.Asp1025= Benign ★★ same type
CSMD3 p.Asp1473= Benign ★★ 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/csmd3-p-arg3025his (accessed [today's date]).

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