Is CCDC50 p.Ala453Val (c.1358C>T) pathogenic?

CCDC50 p.Ala453Val (c.1358C>T) is classified Uncertain significance in CCDC50 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-24). AlphaMissense: likely benign (0.0645); Ultra-rare (popmax 0.01%, amr).

How common is CCDC50 p.Ala453Val (c.1358C>T) in the general population?

CCDC50 p.Ala453Val (c.1358C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about CCDC50 p.Ala453Val (c.1358C>T)?

AlphaMissense predicts likely benign (score 0.0645) — an in-silico prediction, not a clinical call.

CCDC50 p.Ala453Val

c.1358C>T · rs372154907 · VCV2539538

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0645 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0645	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.11	GERP -2.8, phastCons 0.013
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.39 · regional, not allelic
Overall
CADD	13.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A277V vs ClinVar A453V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,996 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00149% 24/1,613,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,999
African / African-American	0.00401%	24,964
Remaining individualsnot grpmax-eligible	0.0032%	31,240
South Asian	0.0011%	91,088
European (non-Finnish)	0.00102%	98,329

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: CCDC50
Protein: p.Ala453Val
Coding: c.1358C>T
MANE Select: NM_178335
dbSNP: rs372154907
Type: single nucleotide variant
Location: chr3:191389531 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.90 · 1 PDB

Full CCDC50 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC50 p.Ala453= Likely benign ★★ same residue
CCDC50 p.Arg138Pro Uncertain significance ★★ ⚠ same type
CCDC50 p.Arg227Gln Uncertain significance ★★ same type
CCDC50 p.Arg227Trp Uncertain significance ★★ same type
CCDC50 p.Arg270Ter Uncertain significance ★★ same type
CCDC50 p.Arg274Ter Uncertain significance ★★ same type
CCDC50 p.Arg305Thr Uncertain significance ★★ same type
CCDC50 p.Arg309Gly 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/ccdc50-p-ala453val (accessed [today's date]).

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