Is AP4E1 p.Ser121Ala (c.361T>G) pathogenic?

AP4E1 p.Ser121Ala (c.361T>G) is classified Uncertain significance in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-22). AlphaMissense: likely benign (0.1293); Very rare (popmax 0.00224%, eas).

How common is AP4E1 p.Ser121Ala (c.361T>G) in the general population?

AP4E1 p.Ser121Ala (c.361T>G) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about AP4E1 p.Ser121Ala (c.361T>G)?

AlphaMissense predicts likely benign (score 0.1293) — an in-silico prediction, not a clinical call.

AP4E1 p.Ser121Ala

c.361T>G · VCV4924955

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1293	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -8.03	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,728 alleles

Overall 0.000124% 2/1,612,018 alleles · very rare exomes 2/1,459,710 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,728
European (non-Finnish)	8.49e-05%	1,178,478

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.Ser121Ala
Coding: c.361T>G
MANE Select: NM_007347
Type: single nucleotide variant
Location: chr15:50923945 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB

Full AP4E1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP4E1 p.Ser121Thr Uncertain significance ★ ⚠ same residue
AP4E1 p.Ser121fs Pathogenic ★ same residue
AP4E1 p.Arg1105Ter Pathogenic ★★ same type
AP4E1 p.Arg304Ter Pathogenic/Likely pathogenic ★★ same type
AP4E1 p.Ala119Ser Uncertain significance ★★ ⚠ same type
AP4E1 p.Ala45Thr Uncertain significance ★★ ⚠ same type
AP4E1 p.Ala475Val Uncertain significance ★★ ⚠ same type
AP4E1 p.Ala65Val Uncertain significance ★★ ⚠ 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/ap4e1-p-ser121ala (accessed [today's date]).

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