Is APTX p.Pro316Ser (c.946C>T) pathogenic?

APTX p.Pro316Ser (c.946C>T) is classified Uncertain significance in APTX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-03). Very rare (popmax 0.00432%, nfe); Associated with Inborn genetic diseases.

What condition is associated with APTX p.Pro316Ser (c.946C>T)?

APTX p.Pro316Ser (c.946C>T) is associated with Inborn genetic diseases (ClinVar).

How common is APTX p.Pro316Ser (c.946C>T) in the general population?

APTX p.Pro316Ser (c.946C>T) is very rare (popmax 0.00432%, nfe) (gnomAD).

APTX p.Pro316Ser

c.946C>T · rs754791634 · VCV1701566

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.829	moderately pathogenic-leaning
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 1.01	unconstrained · MANE · 16 kb · p 0.77 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00432% European (non-Finnish) · 51/1,179,978 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00335% 54/1,613,834 alleles · very rare exomes 47/1,461,864 · genomes 7/151,970 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,137
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,478
African / African-American	0.00134%	74,838

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: APTX
Protein: p.Pro316Ser
Coding: c.946C>T
MANE Select: NM_001195248
dbSNP: rs754791634
Type: single nucleotide variant
Location: chr9:32973581 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 11 PDB

Full APTX 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

Similar variants

APTX p.Pro316= Likely benign ★ same residue
APTX p.Arg29His Uncertain significance ★★ same condition
APTX p.Arg3Gln Uncertain significance ★★ same condition
APTX p.Asn120Ser Uncertain significance ★★ same condition
APTX p.Glu103Lys Uncertain significance ★★ same condition
APTX p.Glu131Lys Uncertain significance ★★ same condition
APTX p.His320Leu Uncertain significance ★★ same condition
APTX p.Ile124Leu Uncertain significance ★★ 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/aptx-p-pro316ser (accessed [today's date]).

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