Is CSMD3 p.Phe2502Leu (c.7506C>A) pathogenic?

CSMD3 p.Phe2502Leu (c.7506C>A) is classified Uncertain significance in CSMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). AlphaMissense: likely pathogenic (0.7447); Ultra-rare (popmax 0.0101%, nfe).

How common is CSMD3 p.Phe2502Leu (c.7506C>A) in the general population?

CSMD3 p.Phe2502Leu (c.7506C>A) is ultra-rare (popmax 0.0101%, nfe) (gnomAD).

What do computational predictors say about CSMD3 p.Phe2502Leu (c.7506C>A)?

AlphaMissense predicts likely pathogenic (score 0.7447) — an in-silico prediction, not a clinical call.

CSMD3 p.Phe2502Leu

c.7506C>A · rs149930140 · VCV3078245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7447 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.7447	likely pathogenic
REVEL	0.109	moderately benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.26	donor loss, 43 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5	GERP 0.16, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 442 kb · p 0.031 · regional, not allelic
Overall
CADD	18.65	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 0.0101% European (non-Finnish) · 119/1,178,628 alleles

Filtering AF 0.0086% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00804%

Overall 0.00757% 122/1,612,418 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0101%	9,904
Remaining individualsnot grpmax-eligible	0.0032%	31,220
South Asian	0.0011%	91,046

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.Phe2502Leu
Coding: c.7506C>A
MANE Select: NM_198123
dbSNP: rs149930140
Type: single nucleotide variant
Location: chr8:112314472 (GRCh38)
Gene constraint: LOEUF 0.464 · pLI 0.97 (gnomAD)
Residue 2502: the cub 14 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-phe2502leu (accessed [today's date]).

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