Is PCNT p.Pro648Ser (c.1942C>T) pathogenic?

PCNT p.Pro648Ser (c.1942C>T) is classified Uncertain significance in PCNT (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely benign (0.0946); Very rare (popmax 0.000508%, nfe); Associated with PCNT-related disorder.

What condition is associated with PCNT p.Pro648Ser (c.1942C>T)?

PCNT p.Pro648Ser (c.1942C>T) is associated with PCNT-related disorder (ClinVar).

How common is PCNT p.Pro648Ser (c.1942C>T) in the general population?

PCNT p.Pro648Ser (c.1942C>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about PCNT p.Pro648Ser (c.1942C>T)?

AlphaMissense predicts likely benign (score 0.0946) — an in-silico prediction, not a clinical call.

PCNT p.Pro648Ser

c.1942C>T · rs774048495 · VCV3036421

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

PCNT-related disorder

Computational evidence

Protein change
AlphaMissense	0.0946	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; 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 -2.5	GERP -2.6
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	0.2	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 0.000508% European (non-Finnish) · 6/1,179,988 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,780 alleles · very rare exomes 6/1,461,560 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,462
European (non-Finnish)grpmax	0.000508%	196,665

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: PCNT
Protein: p.Pro648Ser
Coding: c.1942C>T
MANE Select: NM_006031
dbSNP: rs774048495
Type: single nucleotide variant
Location: chr21:46356979 (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.Pro648Ala Uncertain significance ⚠ same residue
PCNT p.Pro648Leu Uncertain significance ⚠ same residue
PCNT p.Pro648Arg Conflicting classifications of pathogenicity ★ ⚠ 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-pro648ser (accessed [today's date]).

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