Is PCNT p.Asp657Glu (c.1971C>G) pathogenic?

PCNT p.Asp657Glu (c.1971C>G) is classified Conflicting classifications of pathogenicity in PCNT (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.1093); Ultra-rare (popmax 0.0126%, nfe); Associated with microcephalic osteodysplastic primordial dwarfism type II.

What condition is associated with PCNT p.Asp657Glu (c.1971C>G)?

PCNT p.Asp657Glu (c.1971C>G) is associated with microcephalic osteodysplastic primordial dwarfism type II (ClinVar).

How common is PCNT p.Asp657Glu (c.1971C>G) in the general population?

PCNT p.Asp657Glu (c.1971C>G) is ultra-rare (popmax 0.0126%, nfe) (gnomAD).

What do computational predictors say about PCNT p.Asp657Glu (c.1971C>G)?

AlphaMissense predicts likely benign (score 0.1093) — an in-silico prediction, not a clinical call.

PCNT p.Asp657Glu

c.1971C>G · rs150892737 · VCV340474

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0126%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

microcephalic osteodysplastic primordial dwarfism type II

Computational evidence

Protein change
AlphaMissense	0.1093	likely benign
REVEL	0.069	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 -3.1	GERP -2.6
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	0.077	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 0.0126% European (non-Finnish) · 149/1,180,034 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.00954% 154/1,614,038 alleles · ultra-rare exomes 139/1,461,830 · genomes 15/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0126%	7,920
Admixed American	0.00833%	12,002

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.Asp657Glu
Coding: c.1971C>G
MANE Select: NM_006031
dbSNP: rs150892737
Type: single nucleotide variant
Location: chr21:46357008 (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.Asp657= 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-asp657glu (accessed [today's date]).

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