Is AP4E1 p.Gln57= (c.171G>A) pathogenic?

AP4E1 p.Gln57= (c.171G>A) is classified Benign/Likely benign in AP4E1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Low-frequency (popmax 1.74%, afr); Associated with stuttering, familial persistent, 1.

What condition is associated with AP4E1 p.Gln57= (c.171G>A)?

AP4E1 p.Gln57= (c.171G>A) is associated with stuttering, familial persistent, 1, hereditary spastic paraplegia 51, hereditary spastic paraplegia (ClinVar).

How common is AP4E1 p.Gln57= (c.171G>A) in the general population?

AP4E1 p.Gln57= (c.171G>A) is low-frequency (popmax 1.74%, afr) (gnomAD).

AP4E1 p.Gln57=

c.171G>A · rs28463775 · VCV695562

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.74%, afr)

Conditions

stuttering, familial persistent, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.99	GERP 0.72, phastCons 1
Overall
CADD	6.525	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.74% African / African-American · 1,306/75,048 alleles

Filtering AF 1.66% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.63%

Overall 0.0875% 1,413/1,614,068 alleles · low-frequency exomes 654/1,461,762 · genomes 759/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.74%	57
Remaining individualsnot grpmax-eligible	0.08%	1,250
Admixed American	0.07%	1,429
South Asian	0.00329%	30,358
European (non-Finnish)	0.00102%	98,330

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.Gln57=
Coding: c.171G>A
MANE Select: NM_007347
dbSNP: rs28463775
Type: single nucleotide variant
Location: chr15:50912098 (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

Disease context

stuttering, familial persistent, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 51 hereditary spastic paraplegia

Similar variants

AP4E1 p.Arg1105Ter Pathogenic ★★ same condition
AP4E1 p.Asn311Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Asp938Gly Uncertain significance ★★ ⚠ same condition
AP4E1 p.Gln1093Glu Uncertain significance ★★ ⚠ same condition
AP4E1 p.His128Tyr Uncertain significance ★★ ⚠ same condition
AP4E1 p.Ile206Thr Uncertain significance ★★ ⚠ same condition
AP4E1 p.Lys181Gln Uncertain significance ★★ ⚠ same condition
AP4E1 p.Pro717Ser 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-gln57 (accessed [today's date]).

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