Is APBA2 p.Ser723Leu (c.2168C>T) pathogenic?

APBA2 p.Ser723Leu (c.2168C>T) is classified Uncertain significance in APBA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-27). AlphaMissense: likely pathogenic (0.8935); Very rare (popmax 0.00133%, afr).

How common is APBA2 p.Ser723Leu (c.2168C>T) in the general population?

APBA2 p.Ser723Leu (c.2168C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about APBA2 p.Ser723Leu (c.2168C>T)?

AlphaMissense predicts likely pathogenic (score 0.8935) — an in-silico prediction, not a clinical call.

APBA2 p.Ser723Leu

c.2168C>T · rs759806553 · VCV2406088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8935	likely pathogenic
REVEL	0.428	indeterminate
SaProt	LLR -10.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/74,944 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00062% 10/1,613,726 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-Americangrpmax	0.00133%	74,944
South Asian	0.0011%	91,086
European (non-Finnish)	0.000424%	236,009

Ashkenazi Jewish 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: APBA2
Protein: p.Ser723Leu
Coding: c.2168C>T
MANE Select: NM_001353788
dbSNP: rs759806553
Type: single nucleotide variant
Location: chr15:29114006 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.78 (gnomAD)
Structure: AlphaFold pLDDT 59.74
Residue 723: the pdz 2 domain

Full APBA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBA2 p.Ser723= Benign ★ same residue
APBA2 p.Val77Met Uncertain significance ★★ ⚠ same type
APBA2 c.1216-9T>C Benign ★★ same type
APBA2 c.1525-8C>G Likely benign ★★ same type
APBA2 c.1705-9C>T Benign ★★ same type
APBA2 p.Asp87= Benign ★★ same type
APBA2 p.Gly206= Benign ★★ same type
APBA2 p.His127= Benign ★★ 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/apba2-p-ser723leu (accessed [today's date]).

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