Is AP4E1 p.Ser817Phe (c.2450C>T) pathogenic?

AP4E1 p.Ser817Phe (c.2450C>T) is classified Uncertain significance in AP4E1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-20). AlphaMissense: likely benign (0.1036); Ultra-rare (popmax 0.0401%, afr); Associated with Inborn genetic diseases.

What condition is associated with AP4E1 p.Ser817Phe (c.2450C>T)?

AP4E1 p.Ser817Phe (c.2450C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP4E1 p.Ser817Phe (c.2450C>T) in the general population?

AP4E1 p.Ser817Phe (c.2450C>T) is ultra-rare (popmax 0.0401%, afr) (gnomAD).

What do computational predictors say about AP4E1 p.Ser817Phe (c.2450C>T)?

AlphaMissense predicts likely benign (score 0.1036) — an in-silico prediction, not a clinical call.

AP4E1 p.Ser817Phe

c.2450C>T · rs376025300 · VCV1431070

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1036 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1036	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -8.87	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 1.4, phastCons 0.22
Regional constraint	o/e 1.01	unconstrained · MANE · 94 kb · p 0.65 · regional, not allelic
Overall
CADD	21.0	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 0.0401% African / African-American · 30/74,858 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.00236% 38/1,613,418 alleles · ultra-rare exomes 28/1,461,300 · genomes 10/152,118 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0401%	2,495
Remaining individualsnot grpmax-eligible	0.00801%	12,492
Admixed American	0.00501%	19,977

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.Ser817Phe
Coding: c.2450C>T
MANE Select: NM_007347
dbSNP: rs376025300
Type: single nucleotide variant
Location: chr15:50997429 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB
Residue 817: the 'interaction with tepsin' region

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.Ser817Tyr Uncertain significance ★ ⚠ same residue
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

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-ser817phe (accessed [today's date]).

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