Is APBB1 p.Ser695Leu (c.2084C>T) pathogenic?

APBB1 p.Ser695Leu (c.2084C>T) is classified Uncertain significance in APBB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: ambiguous (0.4096); Very rare (popmax 0.0057%, sas).

How common is APBB1 p.Ser695Leu (c.2084C>T) in the general population?

APBB1 p.Ser695Leu (c.2084C>T) is very rare (popmax 0.0057%, sas) (gnomAD).

What do computational predictors say about APBB1 p.Ser695Leu (c.2084C>T)?

AlphaMissense predicts ambiguous (score 0.4096) — an in-silico prediction, not a clinical call.

APBB1 p.Ser695Leu

c.2084C>T · VCV3301624

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4096 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0057%, sas)

Computational evidence

Protein change
AlphaMissense	0.4096	ambiguous
REVEL	0.32	indeterminate
SaProt	LLR -9.58	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 336 bp · p 0.064 · regional, not allelic
Overall
CADD	29.5	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 0.0057% South Asian · 5/87,788 alleles

Filtering AF 0.00216% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00141%

Overall 0.00189% 30/1,583,808 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0057%	17,558
African / African-American	0.00541%	18,473
Admixed American	0.00178%	56,180
European (non-Finnish)	0.00172%	58,168

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.Ser695Leu
Coding: c.2084C>T
MANE Select: NM_001164
Type: single nucleotide variant
Location: chr11:6395583 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.75 · 11 PDB
Residue 695: the pid 2 domain

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-ser695leu (accessed [today's date]).

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