Is CCDC57 p.Ser939Arg (c.2815A>C) pathogenic?

CCDC57 p.Ser939Arg (c.2815A>C) is classified Uncertain significance in CCDC57 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.4015); Very rare (popmax 0.000137%).

How common is CCDC57 p.Ser939Arg (c.2815A>C) in the general population?

CCDC57 p.Ser939Arg (c.2815A>C) is very rare (popmax 0.000137%) (gnomAD).

What do computational predictors say about CCDC57 p.Ser939Arg (c.2815A>C)?

AlphaMissense predicts ambiguous (score 0.4015) — an in-silico prediction, not a clinical call.

CCDC57 p.Ser939Arg

c.2815A>C · VCV4221321

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4015 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000137%)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4015	ambiguous
REVEL	0.104	moderately benign-leaning
SaProt	LLR -7.68	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 0.46, phastCons 1
Overall
CADD	17.63	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S827R vs ClinVar S939R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000137%

Overall 0.000137% 2/1,460,732 alleles · very rare

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: CCDC57
Protein: p.Ser939Arg
Coding: c.2815A>C
MANE Select: NM_001394669
Type: single nucleotide variant
Location: chr17:82127776 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77

Full CCDC57 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC57 p.Ala1009Val Uncertain significance ★ ⚠ same type
CCDC57 p.Ala222Val Uncertain significance ★ ⚠ same type
CCDC57 p.Ala231Val Uncertain significance ★ ⚠ same type
CCDC57 p.Ala329Ser Uncertain significance ★ ⚠ same type
CCDC57 p.Ala469Val Uncertain significance ★ ⚠ same type
CCDC57 p.Ala490Val Uncertain significance ★ ⚠ same type
CCDC57 p.Ala534Thr Uncertain significance ★ ⚠ same type
CCDC57 p.Ala536Pro 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/ccdc57-p-ser939arg (accessed [today's date]).

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