Is PPIC p.Pro34Thr (c.100C>A) pathogenic?

PPIC p.Pro34Thr (c.100C>A) is classified Uncertain significance in PPIC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-04). AlphaMissense: likely pathogenic (0.6058); Ultra-rare (popmax 0.0775%, afr).

How common is PPIC p.Pro34Thr (c.100C>A) in the general population?

PPIC p.Pro34Thr (c.100C>A) is ultra-rare (popmax 0.0775%, afr) (gnomAD).

What do computational predictors say about PPIC p.Pro34Thr (c.100C>A)?

AlphaMissense predicts likely pathogenic (score 0.6058) — an in-silico prediction, not a clinical call.

PPIC p.Pro34Thr

c.100C>A · rs766141474 · VCV2410515

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6058 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0775%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6058	likely pathogenic
REVEL	0.192	benign-leaning
SaProt	LLR -10.99	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.97 · regional, not allelic
Overall
CADD	24.0	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 0.0775% African / African-American · 58/74,838 alleles

Filtering AF 0.0615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0557%

Overall 0.00405% 65/1,606,580 alleles · ultra-rare exomes 34/1,454,356 · genomes 31/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0775%	1,290
Remaining individualsnot grpmax-eligible	0.00161%	62,162
European (non-Finnish)	0.000509%	196,318

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: PPIC
Protein: p.Pro34Thr
Coding: c.100C>A
MANE Select: NM_000943
dbSNP: rs766141474
Type: single nucleotide variant
Location: chr5:123036526 (GRCh38)
Gene constraint: LOEUF 1.354 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.88 · 1 PDB

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

Similar variants

PPIC p.Pro34Leu Uncertain significance ★ ⚠ same residue
PPIC p.Ala137Thr Uncertain significance ★ ⚠ same type
PPIC p.Ala19Val Uncertain significance ★ ⚠ same type
PPIC p.Ala210Thr Uncertain significance ★ ⚠ same type
PPIC p.Arg6Gln Uncertain significance ★ ⚠ same type
PPIC p.Asp185Glu Uncertain significance ★ ⚠ same type
PPIC p.Asp200Gly Uncertain significance ★ ⚠ same type
PPIC p.Glu115Asp Uncertain significance ★ ⚠ same type

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/ppic-p-pro34thr (accessed [today's date]).

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