Is PCNT p.Thr2139Ile (c.6416C>T) pathogenic?

PCNT p.Thr2139Ile (c.6416C>T) is classified Uncertain significance in PCNT (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.1493); Very rare (popmax 0.00401%, afr); Associated with microcephalic osteodysplastic primordial dwarfism type II.

What condition is associated with PCNT p.Thr2139Ile (c.6416C>T)?

PCNT p.Thr2139Ile (c.6416C>T) is associated with microcephalic osteodysplastic primordial dwarfism type II (ClinVar).

How common is PCNT p.Thr2139Ile (c.6416C>T) in the general population?

PCNT p.Thr2139Ile (c.6416C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about PCNT p.Thr2139Ile (c.6416C>T)?

AlphaMissense predicts likely benign (score 0.1493) — an in-silico prediction, not a clinical call.

PCNT p.Thr2139Ile

c.6416C>T · rs886057188 · VCV340516

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1493 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

microcephalic osteodysplastic primordial dwarfism type II

Computational evidence

Protein change
AlphaMissense	0.1493	likely benign
REVEL	0.013	strongly 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 0.12	GERP -3.9, phastCons 0.072
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	7.429	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,814 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,686 alleles · very rare exomes 0/1,461,560 · genomes 3/152,126 · joint denominator

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.Thr2139Ile
Coding: c.6416C>T
MANE Select: NM_006031
dbSNP: rs886057188
Type: single nucleotide variant
Location: chr21:46416334 (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-thr2139ile (accessed [today's date]).

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