Is PPA2 p.Ser61Phe (c.182C>T) pathogenic?

PPA2 p.Ser61Phe (c.182C>T) is classified Likely pathogenic in PPA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2017-09-14). AlphaMissense: likely pathogenic (0.8997); Very rare (popmax 0.0017%, nfe); Associated with sudden cardiac failure, infantile.

What condition is associated with PPA2 p.Ser61Phe (c.182C>T)?

PPA2 p.Ser61Phe (c.182C>T) is associated with sudden cardiac failure, infantile (ClinVar).

How common is PPA2 p.Ser61Phe (c.182C>T) in the general population?

PPA2 p.Ser61Phe (c.182C>T) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about PPA2 p.Ser61Phe (c.182C>T)?

AlphaMissense predicts likely pathogenic (score 0.8997) — an in-silico prediction, not a clinical call.

PPA2 p.Ser61Phe

c.182C>T · rs772083375 · VCV372220

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

sudden cardiac failure, infantile

Computational evidence

Protein change
AlphaMissense	0.8997	likely pathogenic ✓ concordant with ClinVar · top 3% in PPA2
REVEL	0.52	indeterminate
SaProt	LLR -13.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	30.0	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 0.0017% European (non-Finnish) · 20/1,176,166 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000903%

Overall 0.00137% 22/1,606,996 alleles · very rare exomes 22/1,454,778 · genomes 0/152,218 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0017%	58,808
Remaining individualsnot grpmax-eligible	0.00161%	62,248
South Asian	0.00111%	90,158

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: PPA2
Protein: p.Ser61Phe
Coding: c.182C>T
MANE Select: NM_176869
dbSNP: rs772083375
Type: single nucleotide variant
Location: chr4:105456721 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.39
Residue 61: a UniProt-annotated variant site (in scfi; loss of function in regulation of mitochondrial membrane potential)

Full PPA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sudden cardiac failure, infantile — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPA2 p.Arg127Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPA2 p.Glu172Lys Pathogenic/Likely pathogenic ★★ same condition
PPA2 p.Pro228Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPA2 p.Thr159Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPA2 p.Ala130Val Uncertain significance ★★ ⚠ same condition
PPA2 c.442-16A>T Benign ★★ same condition
PPA2 p.Arg9= Benign/Likely benign ★★ same condition
PPA2 p.Lys282Asn Benign ★★ 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/ppa2-p-ser61phe (accessed [today's date]).

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