Is PCNT p.Pro2353Arg (c.7058C>G) pathogenic?

PCNT p.Pro2353Arg (c.7058C>G) is classified Uncertain significance in PCNT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0799); Rare (popmax 0.104%, afr); Associated with Inborn genetic diseases.

What condition is associated with PCNT p.Pro2353Arg (c.7058C>G)?

PCNT p.Pro2353Arg (c.7058C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PCNT p.Pro2353Arg (c.7058C>G) in the general population?

PCNT p.Pro2353Arg (c.7058C>G) is rare (popmax 0.104%, afr) (gnomAD).

What do computational predictors say about PCNT p.Pro2353Arg (c.7058C>G)?

AlphaMissense predicts likely benign (score 0.0799) — an in-silico prediction, not a clinical call.

PCNT p.Pro2353Arg

c.7058C>G · rs139978398 · VCV1353492

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0799 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.104%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0799	likely benign
REVEL	0.011	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 -2.2	GERP -4.3
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	0.028	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 0.104% African / African-American · 78/75,054 alleles

Filtering AF 0.0853% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0785%

Overall 0.00632% 102/1,614,084 alleles · rare exomes 76/1,461,800 · genomes 26/152,284 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.104%	962
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.024%	4,167
South Asian	0.00439%	22,770
European (non-Finnish)	0.000169%	590,005

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.Pro2353Arg
Coding: c.7058C>G
MANE Select: NM_006031
dbSNP: rs139978398
Type: single nucleotide variant
Location: chr21:46422003 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Residue 2353: the 'disordered' region

Full PCNT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PCNT p.Pro2353= Likely benign ★ same residue
PCNT p.Pro2353Thr Uncertain significance ⚠ same residue
PCNT p.Gln910Ter Pathogenic ★★ same condition
PCNT p.Ala1194Val Uncertain significance ★★ ⚠ same condition
PCNT p.Ala1400Thr Uncertain significance ★★ ⚠ same condition
PCNT p.Ala1457Val Uncertain significance ★★ ⚠ same condition
PCNT p.Ala1827Ser Uncertain significance ★★ ⚠ same condition
PCNT p.Ala1827Thr Uncertain significance ★★ ⚠ 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-pro2353arg (accessed [today's date]).

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