Is PPA2 p.Ser313Ter (c.938C>A) pathogenic?

PPA2 p.Ser313Ter (c.938C>A) is classified Conflicting classifications of pathogenicity in PPA2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-01-23). Very rare (popmax 0.00451%, nfe); Associated with PPA2-related disorder.

What condition is associated with PPA2 p.Ser313Ter (c.938C>A)?

PPA2 p.Ser313Ter (c.938C>A) is associated with PPA2-related disorder, sudden cardiac failure, infantile, sudden cardiac failure, alcohol-induced (ClinVar).

How common is PPA2 p.Ser313Ter (c.938C>A) in the general population?

PPA2 p.Ser313Ter (c.938C>A) is very rare (popmax 0.00451%, nfe) (gnomAD).

PPA2 p.Ser313Ter

c.938C>A · rs151331559 · VCV620292

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00451%, nfe)

Conditions

PPA2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 12
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -3.7, phastCons 0.92
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00451% European (non-Finnish) · 53/1,176,094 alleles

Filtering AF 0.00351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00319%

Overall 0.00385% 62/1,609,138 alleles · very rare exomes 55/1,457,016 · genomes 7/152,122 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0109%	9,135
European (non-Finnish)grpmax	0.00451%	22,190
Remaining individualsnot grpmax-eligible	0.00321%	31,136

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser313Ter
Coding: c.938C>A
MANE Select: NM_176869
dbSNP: rs151331559
Type: single nucleotide variant
Location: chr4:105386568 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.39

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

Disease context

PPA2-related disorder

Also linked: sudden cardiac failure, infantile sudden cardiac failure, alcohol-induced

Similar variants

PPA2 p.Ser313Leu Uncertain significance ★ ⚠ same residue
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 p.Thr291Lys Uncertain significance ★★ ⚠ same condition
PPA2 c.442-16A>T 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-ser313ter (accessed [today's date]).

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