Is CDKN1C p.Ser276Leu (c.827C>T) pathogenic?

CDKN1C p.Ser276Leu (c.827C>T) is classified Uncertain significance in CDKN1C (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-20). AlphaMissense: likely benign (0.1989); Very rare (popmax 0.00166%, nfe); Associated with CDKN1C-related disorder.

What condition is associated with CDKN1C p.Ser276Leu (c.827C>T)?

CDKN1C p.Ser276Leu (c.827C>T) is associated with CDKN1C-related disorder, Beckwith-Wiedemann syndrome (ClinVar).

How common is CDKN1C p.Ser276Leu (c.827C>T) in the general population?

CDKN1C p.Ser276Leu (c.827C>T) is very rare (popmax 0.00166%, nfe) (gnomAD).

What do computational predictors say about CDKN1C p.Ser276Leu (c.827C>T)?

AlphaMissense predicts likely benign (score 0.1989) — an in-silico prediction, not a clinical call.

CDKN1C p.Ser276Leu

c.827C>T · rs928007699 · VCV524692

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00166%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDKN1C-related disorder

Computational evidence

Protein change
AlphaMissense	0.1989	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -6.96	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 7.2	GERP -1.5, phastCons 1
Overall
CADD	20.5	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 S287L vs ClinVar S276L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00166% European (non-Finnish) · 19/1,143,372 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000856%

Overall 0.0013% 20/1,540,168 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00168%	59,504
European (non-Finnish)grpmax	0.00166%	60,178

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser276Leu
Coding: c.827C>T
MANE Select: NM_001122630
dbSNP: rs928007699
Type: single nucleotide variant
Location: chr11:2884095 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.93
Residue 276: a UniProt-annotated variant site (in image; pcna binding is disrupted); a UniProt-annotated variant site (in image)

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

Disease context

CDKN1C-related disorder

Also linked: Beckwith-Wiedemann syndrome

Similar variants

CDKN1C p.Ser276Trp Uncertain significance ★ ⚠ same residue
CDKN1C p.Ser276= Likely benign ★ same residue
CDKN1C p.Arg268Ser Likely pathogenic ★★ same condition
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

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-ser276leu (accessed [today's date]).

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