Is PCNT p.Lys347Arg (c.1040A>G) pathogenic?

PCNT p.Lys347Arg (c.1040A>G) is classified Conflicting classifications of pathogenicity in PCNT (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.1094); Rare (popmax 0.763%, eas); Associated with microcephalic osteodysplastic primordial dwarfism type II.

What condition is associated with PCNT p.Lys347Arg (c.1040A>G)?

PCNT p.Lys347Arg (c.1040A>G) is associated with microcephalic osteodysplastic primordial dwarfism type II (ClinVar).

How common is PCNT p.Lys347Arg (c.1040A>G) in the general population?

PCNT p.Lys347Arg (c.1040A>G) is rare (popmax 0.763%, eas) (gnomAD).

What do computational predictors say about PCNT p.Lys347Arg (c.1040A>G)?

AlphaMissense predicts likely benign (score 0.1094) — an in-silico prediction, not a clinical call.

PCNT p.Lys347Arg

c.1040A>G · rs80166001 · VCV159563

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1094 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.763%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

microcephalic osteodysplastic primordial dwarfism type II

Computational evidence

Protein change
AlphaMissense	0.1094	likely benign
REVEL	0.061	moderately 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 4.5	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	22.3	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 0.763% East Asian · 341/44,718 alleles

Filtering AF 0.696% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.67%

Overall 0.0228% 360/1,579,456 alleles · rare exomes 314/1,427,130 · genomes 46/152,326 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.763%	131
Remaining individualsnot grpmax-eligible	0.0212%	4,717
Admixed American	0.00334%	29,962
South Asian	0.00333%	30,074
European (non-Finnish)	8.71e-05%	1,148,652

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.Lys347Arg
Coding: c.1040A>G
MANE Select: NM_006031
dbSNP: rs80166001
Type: single nucleotide variant
Location: chr21:46349019 (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 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
PCNT p.Arg1923Ter 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-lys347arg (accessed [today's date]).

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