Is APBB3 p.Pro136Leu (c.407C>T) pathogenic?

APBB3 p.Pro136Leu (c.407C>T) is classified Uncertain significance in APBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely benign (0.1459); Ultra-rare (popmax 0.011%, sas).

How common is APBB3 p.Pro136Leu (c.407C>T) in the general population?

APBB3 p.Pro136Leu (c.407C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about APBB3 p.Pro136Leu (c.407C>T)?

AlphaMissense predicts likely benign (score 0.1459) — an in-silico prediction, not a clinical call.

APBB3 p.Pro136Leu

c.407C>T · VCV3924930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1459 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1459	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -11.03	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 3,819 bp · p 0.00036 · regional, not allelic
Overall
CADD	33.0	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 0.011% South Asian · 10/91,096 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00638% 103/1,614,022 alleles · ultra-rare exomes 94/1,461,832 · genomes 9/152,190 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,926
South Asiangrpmax	0.011%	9,110
European (non-Finnish)	0.00695%	14,391
African / African-American	0.00267%	37,463
East Asian	0.00223%	44,894
Admixed American	0.00167%	60,008

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: APBB3
Protein: p.Pro136Leu
Coding: c.407C>T
MANE Select: NM_133173
Type: single nucleotide variant
Location: chr5:140562444 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.76 · 2 PDB
Residue 136: the pid 1 domain

Full APBB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBB3 p.Pro136Arg Uncertain significance ★ ⚠ same residue
APBB3 p.Ala135Gly Uncertain significance ★ ⚠ same type
APBB3 p.Ala151Val Uncertain significance ★ ⚠ same type
APBB3 p.Ala163Thr Uncertain significance ★ ⚠ same type
APBB3 p.Ala288Thr Uncertain significance ★ ⚠ same type
APBB3 p.Ala313Val Uncertain significance ★ ⚠ same type
APBB3 p.Ala475Asp Uncertain significance ★ ⚠ same type
APBB3 p.Arg122Cys 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/apbb3-p-pro136leu (accessed [today's date]).

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