Is CDKN1C p.Ala165Pro (c.493G>C) pathogenic?

CDKN1C p.Ala165Pro (c.493G>C) is classified Likely benign in CDKN1C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.0802); Ultra-rare (popmax 0.075%, mid); Associated with Inborn genetic diseases.

What condition is associated with CDKN1C p.Ala165Pro (c.493G>C)?

CDKN1C p.Ala165Pro (c.493G>C) is associated with Inborn genetic diseases, Beckwith-Wiedemann syndrome (ClinVar).

How common is CDKN1C p.Ala165Pro (c.493G>C) in the general population?

CDKN1C p.Ala165Pro (c.493G>C) is ultra-rare (popmax 0.075%, mid) (gnomAD).

What do computational predictors say about CDKN1C p.Ala165Pro (c.493G>C)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

CDKN1C p.Ala165Pro

c.493G>C · rs1312921087 · VCV2199057

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.075%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -3.55	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 -0.25	GERP -0.57
Overall
CADD	5.531	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A176P vs ClinVar A165P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.075% Middle Eastern · 2/2,666 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00554%

Overall 0.00362% 37/1,020,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.075%	1,333
South Asian	0.0047%	21,264
European (non-Finnish)	0.00392%	25,489
East Asian	0.00391%	25,562
African / African-American	0.00179%	55,810

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.Ala165Pro
Coding: c.493G>C
MANE Select: NM_001122630
dbSNP: rs1312921087
Type: single nucleotide variant
Location: chr11:2884964 (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

Also linked: Beckwith-Wiedemann syndrome

Similar variants

CDKN1C p.Ala165Val Uncertain significance ★ ⚠ same residue
CDKN1C p.Ala165= Likely benign ★ same residue
CDKN1C p.Ala165_Val166insAlaProValAlaValAla Uncertain significance ★ same residue
CDKN1C p.Ala165_Leu167delinsLeuAlaPro Likely benign ★ same residue
CDKN1C p.Ala165Leu Likely benign ★ same residue
CDKN1C p.Asp263Asn Pathogenic ★★ ⚠ same condition
CDKN1C p.Cys19Ter Pathogenic/Likely pathogenic ★★ same condition
CDKN1C p.Gln219Ter 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-ala165pro (accessed [today's date]).

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