Is CSMD3 p.Arg528Trp (c.1582C>T) pathogenic?

CSMD3 p.Arg528Trp (c.1582C>T) is classified Uncertain significance in CSMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: ambiguous (0.5355); Very rare (popmax 0.00306%, nfe).

How common is CSMD3 p.Arg528Trp (c.1582C>T) in the general population?

CSMD3 p.Arg528Trp (c.1582C>T) is very rare (popmax 0.00306%, nfe) (gnomAD).

What do computational predictors say about CSMD3 p.Arg528Trp (c.1582C>T)?

AlphaMissense predicts ambiguous (score 0.5355) — an in-silico prediction, not a clinical call.

CSMD3 p.Arg528Trp

c.1582C>T · VCV4007523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5355 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00306%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5355	ambiguous
REVEL	0.459	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.8	GERP -2.9, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 607 kb · p 0.37 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00306% European (non-Finnish) · 36/1,178,104 alleles

Filtering AF 0.00224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00199%

Overall 0.00248% 40/1,611,732 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,214
European (non-Finnish)grpmax	0.00306%	32,725
South Asian	0.0022%	45,512

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: CSMD3
Protein: p.Arg528Trp
Coding: c.1582C>T
MANE Select: NM_198123
Type: single nucleotide variant
Location: chr8:112921678 (GRCh38)
Gene constraint: LOEUF 0.464 · pLI 0.97 (gnomAD)
Residue 528: the sushi 2 domain; a disulfide bond

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-arg528trp (accessed [today's date]).

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