Is PCNT p.Ser1245Arg (c.3735C>A) pathogenic?

PCNT p.Ser1245Arg (c.3735C>A) is classified Conflicting classifications of pathogenicity in PCNT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-24). AlphaMissense: likely pathogenic (0.6854); Rare (popmax 0.136%, eas); Associated with Inborn genetic diseases.

What condition is associated with PCNT p.Ser1245Arg (c.3735C>A)?

PCNT p.Ser1245Arg (c.3735C>A) is associated with Inborn genetic diseases (ClinVar).

How common is PCNT p.Ser1245Arg (c.3735C>A) in the general population?

PCNT p.Ser1245Arg (c.3735C>A) is rare (popmax 0.136%, eas) (gnomAD).

What do computational predictors say about PCNT p.Ser1245Arg (c.3735C>A)?

AlphaMissense predicts likely pathogenic (score 0.6854) — an in-silico prediction, not a clinical call.

PCNT p.Ser1245Arg

c.3735C>A · rs200910675 · VCV3017885

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6854 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6854	likely pathogenic · top 6% in PCNT
REVEL	0.08	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	GERP 4.7, phastCons 0.97
Regional constraint	o/e 1.03	unconstrained · MANE · 121 kb · p 0.027 · regional, not allelic
Overall
CADD	21.7	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 0.136% East Asian · 61/44,878 alleles

Filtering AF 0.109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0986%

Overall 0.00403% 65/1,614,232 alleles · rare exomes 56/1,461,884 · genomes 9/152,348 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.136%	736
Remaining individualsnot grpmax-eligible	0.0032%	31,255
South Asian	0.0022%	45,542

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.Ser1245Arg
Coding: c.3735C>A
MANE Select: NM_006031
dbSNP: rs200910675
Type: single nucleotide variant
Location: chr21:46389326 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Residue 1245: a modified residue (phosphoserine)

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.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
PCNT p.Ala1831Val Uncertain significance ★★ ⚠ same condition
PCNT p.Ala1964Val 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-ser1245arg (accessed [today's date]).

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