Is CCND2 p.Ser271Ter (c.812C>A) pathogenic?

CCND2 p.Ser271Ter (c.812C>A) is classified Likely pathogenic in CCND2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-18). Very rare (popmax 0.00134%, afr); Associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3.

What condition is associated with CCND2 p.Ser271Ter (c.812C>A)?

CCND2 p.Ser271Ter (c.812C>A) is associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (ClinVar).

How common is CCND2 p.Ser271Ter (c.812C>A) in the general population?

CCND2 p.Ser271Ter (c.812C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

CCND2 p.Ser271Ter

c.812C>A · rs776036883 · VCV2504114

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (5 of 5) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.92, phastCons 0.91
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,886 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,613,962 alleles · very rare exomes 5/1,461,862 · genomes 1/152,100 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-Americangrpmax	0.00134%	74,886
European (non-Finnish)	0.000339%	295,002

Ashkenazi Jewish 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: CCND2
Protein: p.Ser271Ter
Coding: c.812C>A
MANE Select: NM_001759
dbSNP: rs776036883
Type: single nucleotide variant
Location: chr12:4299951 (GRCh38)
Gene constraint: LOEUF 0.385 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.98 · 1 PDB
Residue 271: the 'disordered' region; a modified residue (phosphoserine)

Full CCND2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCND2 p.Ser271Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CCND2 p.Gln277Ter Pathogenic/Likely pathogenic ★★ same condition
CCND2 p.Pro281Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
CCND2 p.Thr280Ala Pathogenic ★★ ⚠ same condition
CCND2 p.Thr280Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
CCND2 p.Thr280Ile Pathogenic/Likely pathogenic ★★ ⚠ same condition
CCND2 p.Thr280Pro Pathogenic/Likely pathogenic ★★ ⚠ same condition
CCND2 c.-49T>C Benign ★★ 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/ccnd2-p-ser271ter (accessed [today's date]).

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