Is AP1G1 p.Pro439Ala (c.1315C>G) pathogenic?

AP1G1 p.Pro439Ala (c.1315C>G) is classified Uncertain significance in AP1G1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). AlphaMissense: ambiguous (0.4433); Very rare (popmax 0.000254%, nfe).

How common is AP1G1 p.Pro439Ala (c.1315C>G) in the general population?

AP1G1 p.Pro439Ala (c.1315C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about AP1G1 p.Pro439Ala (c.1315C>G)?

AlphaMissense predicts ambiguous (score 0.4433) — an in-silico prediction, not a clinical call.

AP1G1 p.Pro439Ala

c.1315C>G · VCV4931043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4433 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4433	ambiguous
REVEL	0.256	benign-leaning
SaProt	LLR -7.05	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 17 kb · p 0.62 · regional, not allelic
Overall
CADD	22.6	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 0.000254% European (non-Finnish) · 3/1,179,932 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,920 alleles · very rare exomes 3/1,461,760 · genomes 0/152,160 · joint denominator

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: AP1G1
Protein: p.Pro439Ala
Coding: c.1315C>G
MANE Select: NM_001128
Type: single nucleotide variant
Location: chr16:71750302 (GRCh38)
Gene constraint: LOEUF 0.113 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.56 · 1 PDB

Full AP1G1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1G1 p.Arg15Trp Likely pathogenic ★★ same type
AP1G1 p.Arg416Ter Pathogenic ★★ same type
AP1G1 p.Arg46Ter Uncertain significance ★★ same type
AP1G1 p.Gly120Val Uncertain significance ★★ ⚠ same type
AP1G1 p.His575Asp Uncertain significance ★★ ⚠ same type
AP1G1 p.Ile769Val Uncertain significance ★★ ⚠ same type
AP1G1 c.2367+12A>G Benign ★★ same type
AP1G1 p.Thr179Ser Likely benign ★★ 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/ap1g1-p-pro439ala (accessed [today's date]).

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