Is APBB1 p.Ser449Arg (c.1347C>A) pathogenic?

APBB1 p.Ser449Arg (c.1347C>A) is classified Uncertain significance in APBB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely pathogenic (0.9582); Very rare (popmax 0.00136%, nfe).

How common is APBB1 p.Ser449Arg (c.1347C>A) in the general population?

APBB1 p.Ser449Arg (c.1347C>A) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about APBB1 p.Ser449Arg (c.1347C>A)?

AlphaMissense predicts likely pathogenic (score 0.9582) — an in-silico prediction, not a clinical call.

APBB1 p.Ser449Arg

c.1347C>A · VCV4641572

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9582	likely pathogenic
REVEL	0.264	benign-leaning
SaProt	LLR -11.65	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 15 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	26.3	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 0.00136% European (non-Finnish) · 16/1,180,034 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000991% 16/1,614,042 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: APBB1
Protein: p.Ser449Arg
Coding: c.1347C>A
MANE Select: NM_001164
Type: single nucleotide variant
Location: chr11:6402117 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.75 · 11 PDB
Residue 449: the pid 1 domain; an α-helix

Full APBB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SMPD1 p.Arg498Leu Pathogenic ★★ same type
APBB1 p.Ala371= Benign ★★ same type
APBB1 p.Arg51Cys Benign ★★ ⚠ same type
APBB1 p.Asn126= Benign ★★ same type
APBB1 p.Leu385= Benign ★★ same type
APBB1 p.Met327Val Likely benign ★★ same type
APBB1 c.721+1G>T Uncertain significance ★ same type
APBB1 p.Ala157Val 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/apbb1-p-ser449arg (accessed [today's date]).

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