Is AP1M2 p.Phe348Ser (c.1043T>C) pathogenic?

AP1M2 p.Phe348Ser (c.1043T>C) is classified Uncertain significance in AP1M2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: likely pathogenic (0.9938); Very rare (popmax 0.00111%, sas).

How common is AP1M2 p.Phe348Ser (c.1043T>C) in the general population?

AP1M2 p.Phe348Ser (c.1043T>C) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about AP1M2 p.Phe348Ser (c.1043T>C)?

AlphaMissense predicts likely pathogenic (score 0.9938) — an in-silico prediction, not a clinical call.

AP1M2 p.Phe348Ser

c.1043T>C · VCV3300396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9938	likely pathogenic
REVEL	0.327	indeterminate
SaProt	LLR -15.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 14 kb · p 0.022 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00111% South Asian · 1/90,356 alleles

Overall 6.86e-05% 1/1,456,752 alleles · very rare

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: AP1M2
Protein: p.Phe348Ser
Coding: c.1043T>C
MANE Select: NM_005498
Type: single nucleotide variant
Location: chr19:10577202 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.03
Residue 348: the mhd domain

Full AP1M2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1M2 p.Ala156Gly Uncertain significance ★ ⚠ same type
AP1M2 p.Ala156Thr Uncertain significance ★ ⚠ same type
AP1M2 p.Ala3Val Uncertain significance ★ ⚠ same type
AP1M2 p.Ala405Thr Uncertain significance ★ ⚠ same type
AP1M2 p.Arg104Gln Uncertain significance ★ ⚠ same type
AP1M2 p.Arg148Gln Uncertain significance ★ ⚠ same type
AP1M2 p.Arg148Trp Uncertain significance ★ ⚠ same type
AP1M2 p.Arg19Cys 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/ap1m2-p-phe348ser (accessed [today's date]).

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