Is CCNC p.Arg25His (c.74G>A) pathogenic?

CCNC p.Arg25His (c.74G>A) is classified Uncertain significance in CCNC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.7277); Very rare (popmax 0.00938%, afr).

How common is CCNC p.Arg25His (c.74G>A) in the general population?

CCNC p.Arg25His (c.74G>A) is very rare (popmax 0.00938%, afr) (gnomAD).

What do computational predictors say about CCNC p.Arg25His (c.74G>A)?

AlphaMissense predicts likely pathogenic (score 0.7277) — an in-silico prediction, not a clinical call.

CCNC p.Arg25His

c.74G>A · VCV4650030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7277 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00938%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7277	likely pathogenic
REVEL	0.416	indeterminate
SaProt	LLR -10.11	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 25 kb · p 2.1e-12 · regional, not allelic
Overall
CADD	31.0	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 0.00938% African / African-American · 7/74,590 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00106% 17/1,605,778 alleles · very rare exomes 12/1,453,678 · genomes 5/152,100 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00938%	10,656
Remaining individualsnot grpmax-eligible	0.00161%	62,268
South Asian	0.00112%	89,310
European (non-Finnish)	0.000679%	147,189

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: CCNC
Protein: p.Arg25His
Coding: c.74G>A
MANE Select: NM_005190
Type: single nucleotide variant
Location: chr6:99562907 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI 0.75 (gnomAD)
Structure: AlphaFold pLDDT 92.05 · 36 PDB
Residue 25: an α-helix

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

Similar variants

CCNC p.Arg25Cys Uncertain significance ★ ⚠ same residue
CCNC p.Asp223Gly Uncertain significance ★ ⚠ same type
CCNC p.Gln209His Uncertain significance ★ ⚠ same type
CCNC p.Glu36Ter Uncertain significance ★ same type
CCNC p.Ile15Ser Uncertain significance ★ ⚠ same type
CCNC p.Lys256Arg Uncertain significance ★ ⚠ same type
CCNC p.Lys256Gln Uncertain significance ★ ⚠ same type
CCNC p.Lys56Asn 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/ccnc-p-arg25his (accessed [today's date]).

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