Is CSMD1 p.Arg461= (c.1381C>A) pathogenic?

CSMD1 p.Arg461= (c.1381C>A) is classified Likely benign in CSMD1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-09-05). Very rare (popmax 0.000254%, nfe); Associated with CSMD1-related disorder.

What condition is associated with CSMD1 p.Arg461= (c.1381C>A)?

CSMD1 p.Arg461= (c.1381C>A) is associated with CSMD1-related disorder (ClinVar).

How common is CSMD1 p.Arg461= (c.1381C>A) in the general population?

CSMD1 p.Arg461= (c.1381C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

CSMD1 p.Arg461=

c.1381C>A · rs776858109 · VCV3052396

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

CSMD1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.65	GERP -4.1, phastCons 0.29
Overall
CADD	5.161	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,100 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,459,624 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,438
European (non-Finnish)grpmax	0.000254%	393,034

Remaining individuals 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: CSMD1
Protein: p.Arg461=
Coding: c.1381C>A
MANE Select: NM_033225
dbSNP: rs776858109
Type: single nucleotide variant
Location: chr8:3493690 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Residue 461: the cub 3 domain

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

Disease context

CSMD1-related disorder

Similar variants

CSMD1 p.Arg461Gln Uncertain significance ★ ⚠ same residue
CSMD1 p.Ala1296Val Uncertain significance ★★ ⚠ same condition
CSMD1 p.Asp908Ala Uncertain significance ★★ ⚠ same condition
CSMD1 p.Gln308Leu Uncertain significance ★★ ⚠ same condition
CSMD1 p.Lys1718Asn Uncertain significance ★★ ⚠ same condition
CSMD1 p.Ser319Ter Pathogenic ★ same condition
CSMD1 c.10314+1G>A Uncertain significance ★ same condition
CSMD1 c.1344+31812G>A Uncertain significance ★ same condition

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-arg461 (accessed [today's date]).

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