Is PCNT p.His2125Pro (c.6374A>C) pathogenic?

PCNT p.His2125Pro (c.6374A>C) is classified Benign in PCNT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0504); Common (popmax 44.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with microcephalic osteodysplastic primordial dwarfism type II.

What condition is associated with PCNT p.His2125Pro (c.6374A>C)?

PCNT p.His2125Pro (c.6374A>C) is associated with microcephalic osteodysplastic primordial dwarfism type II (ClinVar).

What do computational predictors say about PCNT p.His2125Pro (c.6374A>C)?

AlphaMissense predicts likely benign (score 0.0504) — an in-silico prediction, not a clinical call.

PCNT p.His2125Pro

Q: How common is PCNT p.His2125Pro (c.6374A>C) in the general population?

PCNT p.His2125Pro (c.6374A>C) is common (popmax 44.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6374A>C · rs35978208 · VCV138622

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0504 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 44.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

microcephalic osteodysplastic primordial dwarfism type II

Computational evidence

Protein change
AlphaMissense	0.0504	likely benign
REVEL	0.06	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 -1.3	GERP -4.3
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	1.478	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 44.3% African / African-American · 33,171/74,862 alleles

Filtering AF 43.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 43.7%

Overall 9.06% 146,192/1,613,722 alleles · common exomes 119,349/1,461,654 · genomes 26,843/152,068 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	44.3%	2
Finnishnot grpmax-eligible	10.4%	10
Remaining individualsnot grpmax-eligible	9.95%	10
South Asian	8.52%	12
Ashkenazi Jewishnot grpmax-eligible	8.5%	12
Middle Eastern	7.46%	13
European (non-Finnish)	7.22%	14
Admixed American	6.83%	15
Amishnot grpmax-eligible	2.74%	36
East Asian	0.23%	436

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.His2125Pro
Coding: c.6374A>C
MANE Select: NM_006031
dbSNP: rs35978208
Type: single nucleotide variant
Location: chr21:46416292 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Residue 2125: a UniProt-annotated variant site (in)

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-his2125pro (accessed [today's date]).

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