Is CCDC25 p.Pro142Ser (c.424C>T) pathogenic?

CCDC25 p.Pro142Ser (c.424C>T) is classified Uncertain significance in CCDC25 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-26). AlphaMissense: likely pathogenic (0.9586); Very rare (popmax 0.00271%, nfe).

How common is CCDC25 p.Pro142Ser (c.424C>T) in the general population?

CCDC25 p.Pro142Ser (c.424C>T) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about CCDC25 p.Pro142Ser (c.424C>T)?

AlphaMissense predicts likely pathogenic (score 0.9586) — an in-silico prediction, not a clinical call.

CCDC25 p.Pro142Ser

c.424C>T · rs758425766 · VCV2377020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9586	likely pathogenic
REVEL	0.329	indeterminate
SaProt	LLR -12.32	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 36 kb · p 5.9e-06 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00271% European (non-Finnish) · 32/1,179,836 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00198% 32/1,613,684 alleles · very rare exomes 32/1,461,650 · genomes 0/152,034 · joint denominator

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: CCDC25
Protein: p.Pro142Ser
Coding: c.424C>T
MANE Select: NM_018246
dbSNP: rs758425766
Type: single nucleotide variant
Location: chr8:27748204 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.83 · 3 PDB

Full CCDC25 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC25 p.Arg140Gln Uncertain significance ★ ⚠ same type
CCDC25 p.Arg140Trp Uncertain significance ★ ⚠ same type
CCDC25 p.Arg153Cys Uncertain significance ★ ⚠ same type
CCDC25 p.Arg153His Uncertain significance ★ ⚠ same type
CCDC25 p.Arg178Lys Uncertain significance ★ ⚠ same type
CCDC25 p.Asn198Asp Uncertain significance ★ ⚠ same type
CCDC25 p.Asn202Ser Uncertain significance ★ ⚠ same type
CCDC25 p.Asn87Ser 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/ccdc25-p-pro142ser (accessed [today's date]).

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