Is AP4E1 p.Pro978Ser (c.2932C>T) pathogenic?

AP4E1 p.Pro978Ser (c.2932C>T) is classified Conflicting classifications of pathogenicity in AP4E1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0868); Rare (popmax 0.238%, sas); Associated with Inborn genetic diseases.

What condition is associated with AP4E1 p.Pro978Ser (c.2932C>T)?

AP4E1 p.Pro978Ser (c.2932C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP4E1 p.Pro978Ser (c.2932C>T) in the general population?

AP4E1 p.Pro978Ser (c.2932C>T) is rare (popmax 0.238%, sas) (gnomAD).

What do computational predictors say about AP4E1 p.Pro978Ser (c.2932C>T)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

AP4E1 p.Pro978Ser

c.2932C>T · rs141278078 · VCV434236

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.238%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -5.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	18.59	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 0.238% South Asian · 217/91,068 alleles

Filtering AF 0.212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.202%

Overall 0.0387% 624/1,613,920 alleles · rare exomes 573/1,461,716 · genomes 51/152,204 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.238%	420
Middle Eastern	0.182%	551
Admixed American	0.0333%	3,000
Remaining individualsnot grpmax-eligible	0.032%	3,125
European (non-Finnish)	0.0293%	3,410
Finnishnot grpmax-eligible	0.0109%	9,143
African / African-American	0.004%	24,995

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: AP4E1
Protein: p.Pro978Ser
Coding: c.2932C>T
MANE Select: NM_007347
dbSNP: rs141278078
Type: single nucleotide variant
Location: chr15:50999099 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB
Residue 978: the 'interaction with tepsin' region; a UniProt-annotated variant site (in stut1; uncertain significance)

Full AP4E1 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

AP4E1 p.Ala65Val Uncertain significance ★★ ⚠ same condition
AP4E1 p.Ala678Val Uncertain significance ★★ ⚠ same condition
AP4E1 p.Arg304Gln Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asp218Gly Uncertain significance ★★ ⚠ same condition
AP4E1 p.Gln1093Glu Uncertain significance ★★ ⚠ same condition
AP4E1 p.Gln375Pro Uncertain significance ★★ ⚠ same condition
AP4E1 p.Gln989Arg Uncertain significance ★★ ⚠ same condition
AP4E1 p.Gln993His 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/ap4e1-p-pro978ser (accessed [today's date]).

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