Is CSMD3 p.Phe3507Ser (c.10520T>C) pathogenic?

CSMD3 p.Phe3507Ser (c.10520T>C) is classified Uncertain significance in CSMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: ambiguous (0.4504); Ultra-rare (popmax 0.0156%, eas).

How common is CSMD3 p.Phe3507Ser (c.10520T>C) in the general population?

CSMD3 p.Phe3507Ser (c.10520T>C) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about CSMD3 p.Phe3507Ser (c.10520T>C)?

AlphaMissense predicts ambiguous (score 0.4504) — an in-silico prediction, not a clinical call.

CSMD3 p.Phe3507Ser

c.10520T>C · rs774419933 · VCV2523738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4504 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Computational evidence

Protein change
AlphaMissense	0.4504	ambiguous
REVEL	0.192	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 442 kb · p 0.031 · regional, not allelic
Overall
CADD	22.3	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 0.0156% East Asian · 7/44,790 alleles

Filtering AF 0.00727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000496% 8/1,613,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,399
African / African-American	0.00134%	74,900

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.Phe3507Ser
Coding: c.10520T>C
MANE Select: NM_198123
dbSNP: rs774419933
Type: single nucleotide variant
Location: chr8:112237297 (GRCh38)
Gene constraint: LOEUF 0.464 · pLI 0.97 (gnomAD)

Full CSMD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSMD3 p.Phe3507Leu Uncertain significance ★ ⚠ same residue
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

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-phe3507ser (accessed [today's date]).

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