Is PCNT p.Pro166= (c.498A>G) pathogenic?

PCNT p.Pro166= (c.498A>G) is classified Benign in PCNT (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Common (popmax 7.91%, mid) — too common for a highly-penetrant pathogenic allele; Associated with microcephalic osteodysplastic primordial dwarfism type II.

What condition is associated with PCNT p.Pro166= (c.498A>G)?

PCNT p.Pro166= (c.498A>G) is associated with microcephalic osteodysplastic primordial dwarfism type II (ClinVar).

PCNT p.Pro166=

Q: How common is PCNT p.Pro166= (c.498A>G) in the general population?

PCNT p.Pro166= (c.498A>G) is common (popmax 7.91%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.498A>G · rs61735824 · VCV138612

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 7.91%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

microcephalic osteodysplastic primordial dwarfism type II

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -0.2
Overall
CADD	1.214	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.91% Middle Eastern · 474/5,994 alleles

Filtering AF 7.32% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.09%

Overall 3.69% 59,031/1,598,466 alleles · common exomes 53,750/1,446,656 · genomes 5,281/151,810 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	11.1%	9
Middle Easterngrpmax	7.91%	13
Amishnot grpmax-eligible	6.25%	16
European (non-Finnish)	4.07%	25
Remaining individualsnot grpmax-eligible	4%	25
Admixed American	2.9%	34
African / African-American	2.31%	43
South Asian	1.48%	67
Finnishnot grpmax-eligible	0.779%	128
East Asian	0.0134%	7,476

Ashkenazi Jewish 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.Pro166=
Coding: c.498A>G
MANE Select: NM_006031
dbSNP: rs61735824
Type: single nucleotide variant
Location: chr21:46334627 (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.Pro166Gln Uncertain significance ★ ⚠ 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-pro166 (accessed [today's date]).

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