Is APBB1IP p.Phe553Ile (c.1657T>A) pathogenic?

APBB1IP p.Phe553Ile (c.1657T>A) is classified Uncertain significance in APBB1IP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.0646); Ultra-rare (popmax 0.0471%, eas).

How common is APBB1IP p.Phe553Ile (c.1657T>A) in the general population?

APBB1IP p.Phe553Ile (c.1657T>A) is ultra-rare (popmax 0.0471%, eas) (gnomAD).

What do computational predictors say about APBB1IP p.Phe553Ile (c.1657T>A)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

APBB1IP p.Phe553Ile

c.1657T>A · rs1225077094 · VCV2517130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0471%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0646	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -7.70	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 -2.2	GERP -3
Regional constraint	o/e 1.08	unconstrained · MANE · 6,746 bp · p 0.12 · regional, not allelic
Overall
CADD	12.74	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 0.0471% East Asian · 15/31,814 alleles

Filtering AF 0.0291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0235%

Overall 0.00176% 25/1,416,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0471%	2,121
Ashkenazi Jewishnot grpmax-eligible	0.0259%	3,861
European (non-Finnish)	0.000365%	273,741

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: APBB1IP
Protein: p.Phe553Ile
Coding: c.1657T>A
MANE Select: NM_019043
dbSNP: rs1225077094
Type: single nucleotide variant
Location: chr10:26567144 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 73.37 · 2 PDB
Residue 553: the 'disordered' region

Full APBB1IP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBB1IP p.Phe553Ser Uncertain significance ★ ⚠ same residue
APBB1IP p.Ala617Thr Benign ★★ same type
APBB1IP p.Ala622Val Benign ★★ same type
APBB1IP p.Arg429Trp Benign ★★ ⚠ same type
APBB1IP p.Phe208= Benign ★★ same type
APBB1IP p.Ala118Pro Uncertain significance ★ ⚠ same type
APBB1IP p.Ala354Val Uncertain significance ★ ⚠ same type
APBB1IP p.Ala41Thr 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/apbb1ip-p-phe553ile (accessed [today's date]).

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