Is AP4M1 p.Pro221Ser (c.661C>T) pathogenic?

AP4M1 p.Pro221Ser (c.661C>T) is classified Uncertain significance in AP4M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely benign (0.121); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AP4M1 p.Pro221Ser (c.661C>T)?

AP4M1 p.Pro221Ser (c.661C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP4M1 p.Pro221Ser (c.661C>T) in the general population?

AP4M1 p.Pro221Ser (c.661C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about AP4M1 p.Pro221Ser (c.661C>T)?

AlphaMissense predicts likely benign (score 0.121) — an in-silico prediction, not a clinical call.

AP4M1 p.Pro221Ser

c.661C>T · VCV3923436

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.121 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.121	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -6.89	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 2.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,164 bp · p 0.093 · regional, not allelic
Overall
CADD	23.3	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 0.000339% European (non-Finnish) · 4/1,180,032 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,876 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.Pro221Ser
Coding: c.661C>T
MANE Select: NM_004722
Type: single nucleotide variant
Location: chr7:100104928 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16 · 6 PDB
Residue 221: the mhd domain

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.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.Arg271Cys Uncertain significance ★★ ⚠ same condition
AP4M1 p.Arg283Trp Uncertain significance ★★ ⚠ same condition
AP4M1 p.Arg367Trp 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-pro221ser (accessed [today's date]).

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