Is CCNH p.Lys138Arg (c.413A>G) pathogenic?

CCNH p.Lys138Arg (c.413A>G) is classified Benign in CCNH (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0918); Common (popmax 7.71%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CCNH p.Lys138Arg (c.413A>G)?

AlphaMissense predicts likely benign (score 0.0918) — an in-silico prediction, not a clinical call.

CCNH p.Lys138Arg

Q: How common is CCNH p.Lys138Arg (c.413A>G) in the general population?

CCNH p.Lys138Arg (c.413A>G) is common (popmax 7.71%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.413A>G · rs2266691 · VCV768017

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0918 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.71%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0918	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -6.72	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 6.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 18 kb · p 0.18 · regional, not allelic
Overall
CADD	21.2	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 7.71% African / African-American · 5,777/74,954 alleles

Filtering AF 7.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.47%

Overall 0.43% 6,944/1,613,060 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.71%	13
Admixed American	0.59%	170
Middle Eastern	0.528%	189
Remaining individualsnot grpmax-eligible	0.506%	198
European (non-Finnish)	0.0385%	2,597
South Asian	0.0121%	8,277

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.Lys138Arg
Coding: c.413A>G
MANE Select: NM_001239
dbSNP: rs2266691
Type: single nucleotide variant
Location: chr5:87408088 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.26 · 49 PDB
Residue 138: a UniProt-annotated variant site (in); an α-helix

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-lys138arg (accessed [today's date]).

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