Is PCNT p.Ser2191Pro (c.6571T>C) pathogenic?

PCNT p.Ser2191Pro (c.6571T>C) is classified Benign/Likely benign in PCNT (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0891); Common (popmax 8.28%, mid) — too common for a highly-penetrant pathogenic allele; Associated with microcephalic osteodysplastic primordial dwarfism type II.

What condition is associated with PCNT p.Ser2191Pro (c.6571T>C)?

PCNT p.Ser2191Pro (c.6571T>C) is associated with microcephalic osteodysplastic primordial dwarfism type II (ClinVar).

What do computational predictors say about PCNT p.Ser2191Pro (c.6571T>C)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

PCNT p.Ser2191Pro

Q: How common is PCNT p.Ser2191Pro (c.6571T>C) in the general population?

PCNT p.Ser2191Pro (c.6571T>C) is common (popmax 8.28%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6571T>C · rs34151633 · VCV159634

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.28%, mid) — 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	0.0891	likely benign
REVEL	0.025	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 0.015	GERP -2.1
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	11.56	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 8.28% Middle Eastern · 502/6,062 alleles

Filtering AF 7.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.45%

Overall 4.05% 65,323/1,614,058 alleles · common exomes 60,161/1,461,724 · genomes 5,162/152,334 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	14.7%	7
Middle Easterngrpmax	8.28%	12
Amishnot grpmax-eligible	6.37%	16
Remaining individualsnot grpmax-eligible	4.53%	22
European (non-Finnish)	4.42%	23
Admixed American	3.25%	31
South Asian	1.84%	54
African / African-American	1.66%	60
Finnishnot grpmax-eligible	0.818%	122
East Asian	0.0111%	8,976

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.Ser2191Pro
Coding: c.6571T>C
MANE Select: NM_006031
dbSNP: rs34151633
Type: single nucleotide variant
Location: chr21:46416489 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Residue 2191: the 'disordered' region; 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 p.Ser2191Tyr 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-ser2191pro (accessed [today's date]).

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