Is PCNT p.Ala2149Ser (c.6445G>T) pathogenic?

PCNT p.Ala2149Ser (c.6445G>T) is classified Uncertain significance in PCNT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-01). AlphaMissense: likely benign (0.0888); Very rare (popmax 0.0022%, sas); Associated with PCNT-related disorder.

What condition is associated with PCNT p.Ala2149Ser (c.6445G>T)?

PCNT p.Ala2149Ser (c.6445G>T) is associated with PCNT-related disorder (ClinVar).

How common is PCNT p.Ala2149Ser (c.6445G>T) in the general population?

PCNT p.Ala2149Ser (c.6445G>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about PCNT p.Ala2149Ser (c.6445G>T)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

PCNT p.Ala2149Ser

c.6445G>T · rs753398642 · VCV2635383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

PCNT-related disorder

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.4	GERP -0.74, phastCons 0.003
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	2.797	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,088 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000124% 2/1,614,062 alleles · very rare exomes 2/1,461,830 · genomes 0/152,232 · joint denominator

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.Ala2149Ser
Coding: c.6445G>T
MANE Select: NM_006031
dbSNP: rs753398642
Type: single nucleotide variant
Location: chr21:46416363 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)

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

Disease context

PCNT-related disorder

Similar variants

PCNT p.Ala2149Val Uncertain significance ⚠ same residue
PCNT p.Ala2149Thr Uncertain significance ★ ⚠ same residue
PCNT p.Ala2149= Likely benign ★ same residue
PCNT c.3313-2A>C Likely pathogenic ★★ same condition
PCNT c.7024+1G>A Likely pathogenic ★★ same condition
PCNT c.7691-1G>A Likely pathogenic ★★ same condition
PCNT c.8065-1G>C Likely pathogenic ★★ same condition
PCNT p.Arg3236Ter Pathogenic/Likely 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/pcnt-p-ala2149ser (accessed [today's date]).

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