Is AP4M1 p.Arg271Pro (c.812G>C) pathogenic?

AP4M1 p.Arg271Pro (c.812G>C) is classified Uncertain significance in AP4M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). AlphaMissense: likely pathogenic (0.853); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AP4M1 p.Arg271Pro (c.812G>C)?

AP4M1 p.Arg271Pro (c.812G>C) is associated with Inborn genetic diseases (ClinVar).

How common is AP4M1 p.Arg271Pro (c.812G>C) in the general population?

AP4M1 p.Arg271Pro (c.812G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about AP4M1 p.Arg271Pro (c.812G>C)?

AlphaMissense predicts likely pathogenic (score 0.853) — an in-silico prediction, not a clinical call.

AP4M1 p.Arg271Pro

c.812G>C · VCV3404587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.853	likely pathogenic
REVEL	0.208	benign-leaning
SaProt	LLR -10.66	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,164 bp · p 0.093 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,972 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,872 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: AP4M1
Protein: p.Arg271Pro
Coding: c.812G>C
MANE Select: NM_004722
Type: single nucleotide variant
Location: chr7:100105324 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB
Residue 271: the mhd domain; a β-strand

Full AP4M1 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

AP4M1 p.Arg271Cys Uncertain significance ★★ ⚠ same residue
AP4M1 p.Arg271His Benign ★★ same residue
AP4M1 p.Cys319Arg Pathogenic/Likely pathogenic ★★ same condition
AP4M1 c.673+6G>A Uncertain significance ★★ same condition
AP4M1 c.*449G>A Uncertain significance ★★ ⚠ same condition
AP4M1 p.Ala397Val Uncertain significance ★★ ⚠ same condition
AP4M1 p.Arg172His Uncertain significance ★★ same condition
AP4M1 p.Arg283Trp 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/ap4m1-p-arg271pro (accessed [today's date]).

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