Is CDKN1C p.Ala165Val (c.494C>T) pathogenic?

CDKN1C p.Ala165Val (c.494C>T) is classified Uncertain significance in CDKN1C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-16). AlphaMissense: likely benign (0.1529); Ultra-rare (popmax 0.073%, mid); Associated with Inborn genetic diseases.

What condition is associated with CDKN1C p.Ala165Val (c.494C>T)?

CDKN1C p.Ala165Val (c.494C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CDKN1C p.Ala165Val (c.494C>T) in the general population?

CDKN1C p.Ala165Val (c.494C>T) is ultra-rare (popmax 0.073%, mid) (gnomAD).

What do computational predictors say about CDKN1C p.Ala165Val (c.494C>T)?

AlphaMissense predicts likely benign (score 0.1529) — an in-silico prediction, not a clinical call.

CDKN1C p.Ala165Val

c.494C>T · rs1383784539 · VCV2514768

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1529 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.073%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1529	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -9.12	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 0.77	GERP -0.68, phastCons 0.001
Overall
CADD	12.56	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A176V vs ClinVar A165V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.073% Middle Eastern · 2/2,738 alleles

Filtering AF 0.0129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00533%

Overall 0.00353% 37/1,047,576 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.073%	1,369
South Asian	0.00456%	21,934
European (non-Finnish)	0.00395%	25,312
African / African-American	0.0017%	58,914

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.Ala165Val
Coding: c.494C>T
MANE Select: NM_001122630
dbSNP: rs1383784539
Type: single nucleotide variant
Location: chr11:2884963 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 165: the '9 x 4 aa repeats of p-a-p-a' region

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

Similar variants

CDKN1C p.Ala165Pro Likely benign ★★ same residue
CDKN1C p.Ala165= Likely benign ★ same residue
CDKN1C p.Asp263Asn Pathogenic ★★ ⚠ same condition
CDKN1C c.-10-7T>C Uncertain significance ★★ ⚠ same condition
CDKN1C p.Ala111Thr Uncertain significance ★★ ⚠ same condition
CDKN1C p.Ala148Pro Uncertain significance ★★ ⚠ same condition
CDKN1C p.Ala168Val Uncertain significance ★★ ⚠ same condition
CDKN1C p.Arg238Cys Uncertain significance ★★ ⚠ 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-ala165val (accessed [today's date]).

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