Is CSMD2 p.Leu1981Phe (c.5941C>T) pathogenic?

CSMD2 p.Leu1981Phe (c.5941C>T) is classified Uncertain significance in CSMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely pathogenic (0.7774); Very rare (popmax 0.00134%, afr).

How common is CSMD2 p.Leu1981Phe (c.5941C>T) in the general population?

CSMD2 p.Leu1981Phe (c.5941C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CSMD2 p.Leu1981Phe (c.5941C>T)?

AlphaMissense predicts likely pathogenic (score 0.7774) — an in-silico prediction, not a clinical call.

CSMD2 p.Leu1981Phe

c.5941C>T · VCV3836794

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7774 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Computational evidence

Protein change
AlphaMissense	0.7774	likely pathogenic
REVEL	0.612	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 331 kb · p 5.5e-29 · regional, not allelic
Overall
CADD	29.4	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 L1941F vs ClinVar L1981F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,860 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00118% 19/1,612,354 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0156%	6,404
African / African-Americangrpmax	0.00134%	74,860
European (non-Finnish)	0.000679%	147,319

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu1981Phe
Coding: c.5941C>T
MANE Select: NM_001281956
Type: single nucleotide variant
Location: chr1:33617504 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Residue 1981: a disulfide bond; the cub 12 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-leu1981phe (accessed [today's date]).

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