Is CCDC57 p.His145Asp (c.433C>G) pathogenic?

CCDC57 p.His145Asp (c.433C>G) is classified Uncertain significance in CCDC57 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.3502); Very rare (popmax 0.00848%, nfe).

How common is CCDC57 p.His145Asp (c.433C>G) in the general population?

CCDC57 p.His145Asp (c.433C>G) is very rare (popmax 0.00848%, nfe) (gnomAD).

What do computational predictors say about CCDC57 p.His145Asp (c.433C>G)?

AlphaMissense predicts ambiguous (score 0.3502) — an in-silico prediction, not a clinical call.

CCDC57 p.His145Asp

c.433C>G · VCV4221309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3502 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00848%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3502	ambiguous
REVEL	0.083	moderately benign-leaning
SaProt	LLR -9.78	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 11	GERP 4.8, phastCons 1
Overall
CADD	22.5	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 0.00848% European (non-Finnish) · 100/1,178,620 alleles

Filtering AF 0.00709% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00645% 104/1,611,892 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00848%	11,786
Admixed American	0.00334%	29,912
Remaining individualsnot grpmax-eligible	0.0032%	31,204

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.His145Asp
Coding: c.433C>G
MANE Select: NM_001394669
Type: single nucleotide variant
Location: chr17:82198397 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77
Residue 145: the 'centrosomal targeting domain' region

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-his145asp (accessed [today's date]).

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