Is PCNT p.Ala2985Pro (c.8953G>C) pathogenic?

PCNT p.Ala2985Pro (c.8953G>C) is classified Uncertain significance in PCNT (ClinVar, Single submitter, 2 submitters; last evaluated 2022-07-25). AlphaMissense: likely pathogenic (0.8987); Ultra-rare (popmax 0.0133%, afr).

How common is PCNT p.Ala2985Pro (c.8953G>C) in the general population?

PCNT p.Ala2985Pro (c.8953G>C) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about PCNT p.Ala2985Pro (c.8953G>C)?

AlphaMissense predicts likely pathogenic (score 0.8987) — an in-silico prediction, not a clinical call.

PCNT p.Ala2985Pro

c.8953G>C · rs188889473 · VCV1425078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8987 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.8987	likely pathogenic · top 2% in PCNT
REVEL	0.181	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 0.99
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/75,044 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.000745% 12/1,610,858 alleles · ultra-rare exomes 9/1,458,550 · genomes 3/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,504
European (non-Finnish)	0.00017%	589,918

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: PCNT
Protein: p.Ala2985Pro
Coding: c.8953G>C
MANE Select: NM_006031
dbSNP: rs188889473
Type: single nucleotide variant
Location: chr21:46436105 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Residue 2985: the 'interaction with nek2' region

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

Similar variants

PCNT p.Ala2985= Likely benign ★★ same residue
PCNT c.1032+1G>A Pathogenic/Likely pathogenic ★★ same type
PCNT c.1680-1G>C Likely pathogenic ★★ same type
PCNT c.3313-2A>C Likely pathogenic ★★ same type
PCNT c.5995-2A>C Likely pathogenic ★★ same type
PCNT c.7024+1G>A Likely pathogenic ★★ same type
PCNT c.7024+1G>C Likely pathogenic ★★ same type
PCNT c.7691-1G>A Likely pathogenic ★★ same type

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/pcnt-p-ala2985pro (accessed [today's date]).

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