Is CCNH p.Pro42Leu (c.125C>T) pathogenic?

CCNH p.Pro42Leu (c.125C>T) is classified Uncertain significance in CCNH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0837); Very rare (popmax 0.00224%, eas).

How common is CCNH p.Pro42Leu (c.125C>T) in the general population?

CCNH p.Pro42Leu (c.125C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about CCNH p.Pro42Leu (c.125C>T)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

CCNH p.Pro42Leu

c.125C>T · VCV4222108

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -7.79	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 8.7	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 18 kb · p 0.18 · regional, not allelic
Overall
CADD	23.5	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,592 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000499% 8/1,604,540 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,592
European (non-Finnish)	0.000595%	168,101

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: CCNH
Protein: p.Pro42Leu
Coding: c.125C>T
MANE Select: NM_001239
Type: single nucleotide variant
Location: chr5:87411339 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.26 · 49 PDB

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

Similar variants

RASA1 c.1698+1G>A Pathogenic/Likely pathogenic ★★ same type
RASA1 c.2012-2A>G Pathogenic/Likely pathogenic ★★ same type
RASA1 c.2603+1G>A Pathogenic ★★ same type
RASA1 c.2691-1G>T Pathogenic/Likely pathogenic ★★ same type
RASA1 c.2925+1G>T Pathogenic ★★ same type
RASA1 c.899+1G>T Likely pathogenic ★★ same type
RASA1 p.Arg1010Ter Pathogenic ★★ same type
RASA1 p.Arg285Ter Pathogenic ★★ 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/ccnh-p-pro42leu (accessed [today's date]).

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