Is CDKN1C p.Ala174= (c.522T>C) pathogenic?

CDKN1C p.Ala174= (c.522T>C) is classified Benign/Likely benign in CDKN1C (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 35.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with CDKN1C p.Ala174= (c.522T>C)?

CDKN1C p.Ala174= (c.522T>C) is associated with Inborn genetic diseases, Beckwith-Wiedemann syndrome (ClinVar).

CDKN1C p.Ala174=

Q: How common is CDKN1C p.Ala174= (c.522T>C) in the general population?

CDKN1C p.Ala174= (c.522T>C) is common (popmax 35.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.522T>C · rs191294997 · VCV158189

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 35.7%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.4	GERP -0.91
Overall
CADD	4.584	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 35.7% African / African-American · 18,476/51,784 alleles

Filtering AF 35.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.1%

Overall 21.2% 190,519/899,522 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	35.7%	3
Amishnot grpmax-eligible	25.7%	4
Admixed American	25.1%	4
European (non-Finnish)	20.5%	5
Remaining individualsnot grpmax-eligible	20.3%	5
Finnishnot grpmax-eligible	19.3%	5
East Asian	16.3%	6
Ashkenazi Jewishnot grpmax-eligible	15.7%	6
South Asian	15.3%	7
Middle Eastern	15.1%	7

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: CDKN1C
Protein: p.Ala174=
Coding: c.522T>C
MANE Select: NM_001122630
dbSNP: rs191294997
Type: single nucleotide variant
Location: chr11:2884935 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 174: the '9 x 4 aa repeats of p-a-p-a' region; a UniProt-annotated variant site (in several cancers)

Full CDKN1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Beckwith-Wiedemann syndrome

Similar variants

CDKN1C p.Ala174Gly Uncertain significance ★ ⚠ same residue
CDKN1C p.Ala174_Pro175insLeuAlaProAlaProAlaProAla Uncertain significance ★ same residue
CDKN1C p.Asp263Asn Pathogenic ★★ ⚠ same condition
CDKN1C p.Cys19Ter Pathogenic/Likely pathogenic ★★ same condition
CDKN1C p.Gln219Ter Pathogenic ★★ same condition
CDKN1C p.Gln221Ter Pathogenic ★★ same condition
CDKN1C p.Gln230Ter Pathogenic ★★ same condition
CDKN1C p.Glu119Ter Pathogenic ★★ same condition

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/cdkn1c-p-ala174 (accessed [today's date]).

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