Is PPCS p.Ile285Thr (c.854T>C) pathogenic?

PPCS p.Ile285Thr (c.854T>C) is classified Conflicting classifications of pathogenicity in PPCS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-24). AlphaMissense: likely benign (0.0602); Ultra-rare (popmax 0.0757%, sas); Associated with Inborn genetic diseases.

What condition is associated with PPCS p.Ile285Thr (c.854T>C)?

PPCS p.Ile285Thr (c.854T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PPCS p.Ile285Thr (c.854T>C) in the general population?

PPCS p.Ile285Thr (c.854T>C) is ultra-rare (popmax 0.0757%, sas) (gnomAD).

What do computational predictors say about PPCS p.Ile285Thr (c.854T>C)?

AlphaMissense predicts likely benign (score 0.0602) — an in-silico prediction, not a clinical call.

PPCS p.Ile285Thr

c.854T>C · rs780467070 · VCV1374099

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0602 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0757%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0602	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -8.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.5	GERP -2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 2,669 bp · p 5.9e-05 · regional, not allelic
Overall
CADD	15.63	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0757% South Asian · 69/91,092 alleles

Filtering AF 0.0613% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0561%

Overall 0.00892% 144/1,613,966 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0757%	1,320
Middle Eastern	0.0164%	6,080
Admixed American	0.0117%	8,570
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.00517%	19,345
African / African-American	0.00134%	74,884

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: PPCS
Protein: p.Ile285Thr
Coding: c.854T>C
MANE Select: NM_001395517 · reported on NM_024664
dbSNP: rs780467070
Type: single nucleotide variant
Location: chr1:42459844 (GRCh38)

Full PPCS 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

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/ppcs-p-ile285thr (accessed [today's date]).

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