Is AP4B1 p.Met100Val (c.298A>G) pathogenic?

AP4B1 p.Met100Val (c.298A>G) is classified Uncertain significance in AP4B1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-02). AlphaMissense: likely benign (0.187); Very rare (popmax 0.00659%, sas); Associated with Inborn genetic diseases.

What condition is associated with AP4B1 p.Met100Val (c.298A>G)?

AP4B1 p.Met100Val (c.298A>G) is associated with Inborn genetic diseases, hereditary spastic paraplegia 47 (ClinVar).

How common is AP4B1 p.Met100Val (c.298A>G) in the general population?

AP4B1 p.Met100Val (c.298A>G) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about AP4B1 p.Met100Val (c.298A>G)?

AlphaMissense predicts likely benign (score 0.187) — an in-silico prediction, not a clinical call.

AP4B1 p.Met100Val

c.298A>G · rs752682155 · VCV1362639

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.187	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -4.18	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 4.2	GERP 0.97, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 9,649 bp · p 0.84 · regional, not allelic
Overall
CADD	22.1	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 0.00659% South Asian · 6/91,072 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00403% 65/1,613,808 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,179
European (non-Finnish)	0.00441%	22,693
African / African-American	0.004%	24,976
Remaining individualsnot grpmax-eligible	0.0032%	31,226
East Asian	0.00223%	44,900
Admixed American	0.00167%	59,998

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: AP4B1
Protein: p.Met100Val
Coding: c.298A>G
MANE Select: NM_001253852
dbSNP: rs752682155
Type: single nucleotide variant
Location: chr1:113902678 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.56 · 5 PDB

Full AP4B1 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

Also linked: hereditary spastic paraplegia 47

Similar variants

AP4B1 p.Met100Thr Uncertain significance ★ ⚠ same residue
AP4B1 c.114-2A>C Pathogenic ★★ same condition
AP4B1 c.114-2A>G Pathogenic ★★ same condition
AP4B1 p.Arg102Ter Pathogenic ★★ same condition
AP4B1 p.Arg206Ter Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Arg353Ter Pathogenic/Likely pathogenic ★★ same condition
AP4B1 p.Arg393Ter Pathogenic ★★ same condition
AP4B1 p.Arg406Ter Pathogenic/Likely pathogenic ★★ 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/ap4b1-p-met100val (accessed [today's date]).

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