Is PPIC p.Asp185Glu (c.555C>A) pathogenic?

PPIC p.Asp185Glu (c.555C>A) is classified Uncertain significance in PPIC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-20). AlphaMissense: likely pathogenic (0.9129); Very rare (popmax 0.00373%, nfe).

How common is PPIC p.Asp185Glu (c.555C>A) in the general population?

PPIC p.Asp185Glu (c.555C>A) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about PPIC p.Asp185Glu (c.555C>A)?

AlphaMissense predicts likely pathogenic (score 0.9129) — an in-silico prediction, not a clinical call.

PPIC p.Asp185Glu

c.555C>A · rs777380161 · VCV2397644

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9129 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9129	likely pathogenic
REVEL	0.242	benign-leaning
SaProt	LLR -10.75	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 3.9	GERP 1.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.97 · regional, not allelic
Overall
CADD	22.4	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 0.00373% European (non-Finnish) · 44/1,180,010 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00291% 47/1,613,966 alleles · very rare exomes 45/1,461,832 · genomes 2/152,134 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,818
African / African-American	0.00267%	37,453
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Asp185Glu
Coding: c.555C>A
MANE Select: NM_000943
dbSNP: rs777380161
Type: single nucleotide variant
Location: chr5:123023959 (GRCh38)
Gene constraint: LOEUF 1.354 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.88 · 1 PDB
Residue 185: the ppiase cyclophilin-type domain

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

Similar variants

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.Asp200Gly Uncertain significance ★ ⚠ same type
PPIC p.Glu115Asp Uncertain significance ★ ⚠ same type
PPIC p.Gly130Glu Uncertain significance ★ ⚠ same type
PPIC p.Gly25Ala 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-asp185glu (accessed [today's date]).

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