Is PCNT p.Val161Ile (c.481G>A) pathogenic?

PCNT p.Val161Ile (c.481G>A) is classified Uncertain significance in PCNT (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-05). AlphaMissense: likely benign (0.0749); Very rare (popmax 0.00172%, nfe); Associated with microcephalic osteodysplastic primordial dwarfism type II.

What condition is associated with PCNT p.Val161Ile (c.481G>A)?

PCNT p.Val161Ile (c.481G>A) is associated with microcephalic osteodysplastic primordial dwarfism type II (ClinVar).

How common is PCNT p.Val161Ile (c.481G>A) in the general population?

PCNT p.Val161Ile (c.481G>A) is very rare (popmax 0.00172%, nfe) (gnomAD).

What do computational predictors say about PCNT p.Val161Ile (c.481G>A)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

PCNT p.Val161Ile

c.481G>A · rs555841008 · VCV896697

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00172%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

microcephalic osteodysplastic primordial dwarfism type II

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.02	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 -3.2	GERP -0.2
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	0.016	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 0.00172% European (non-Finnish) · 20/1,160,104 alleles

Filtering AF 0.00113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000915%

Overall 0.00145% 23/1,588,046 alleles · very rare exomes 18/1,442,286 · genomes 5/145,760 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00172%	58,005
Admixed American	0.00171%	58,646
Remaining individualsnot grpmax-eligible	0.00163%	61,246
African / African-American	0.00135%	73,856

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.Val161Ile
Coding: c.481G>A
MANE Select: NM_006031
dbSNP: rs555841008
Type: single nucleotide variant
Location: chr21:46334610 (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

microcephalic osteodysplastic primordial dwarfism type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PCNT p.Val161= Likely benign ★ same residue
PCNT c.1032+1G>A Pathogenic/Likely pathogenic ★★ same condition
PCNT c.1680-1G>C Likely pathogenic ★★ same condition
PCNT c.5995-2A>C Likely pathogenic ★★ same condition
PCNT c.7024+1G>C Likely pathogenic ★★ same condition
PCNT c.7691-1G>A Likely pathogenic ★★ same condition
PCNT c.9624-2A>G Likely pathogenic ★★ same condition
PCNT p.Arg1730Ter 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-val161ile (accessed [today's date]).

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