Is CSMD2 p.Glu995Lys (c.2983G>A) pathogenic?

CSMD2 p.Glu995Lys (c.2983G>A) is classified Uncertain significance in CSMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: likely benign (0.17); Very rare (popmax 0.00879%, sas).

How common is CSMD2 p.Glu995Lys (c.2983G>A) in the general population?

CSMD2 p.Glu995Lys (c.2983G>A) is very rare (popmax 0.00879%, sas) (gnomAD).

What do computational predictors say about CSMD2 p.Glu995Lys (c.2983G>A)?

AlphaMissense predicts likely benign (score 0.17) — an in-silico prediction, not a clinical call.

CSMD2 p.Glu995Lys

c.2983G>A · rs757085822 · VCV3078165

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.17 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00879%, sas)

Computational evidence

Protein change
AlphaMissense	0.17	likely benign
REVEL	0.414	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	32.0	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 E955K vs ClinVar E995K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00879% South Asian · 8/91,032 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00105% 17/1,612,956 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00879%	11,379
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
African / African-American	0.00267%	37,436
Remaining individualsnot grpmax-eligible	0.0016%	62,436
European (non-Finnish)	0.000424%	235,827

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.Glu995Lys
Coding: c.2983G>A
MANE Select: NM_001281956
dbSNP: rs757085822
Type: single nucleotide variant
Location: chr1:33724215 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Residue 995: the cub 6 domain

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-glu995lys (accessed [today's date]).

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