Is ABCA8 p.Leu728Pro (c.2183T>C) pathogenic?

ABCA8 p.Leu728Pro (c.2183T>C) is classified Uncertain significance in ABCA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely pathogenic (0.7283); Rare (popmax 0.2%, mid).

How common is ABCA8 p.Leu728Pro (c.2183T>C) in the general population?

ABCA8 p.Leu728Pro (c.2183T>C) is rare (popmax 0.2%, mid) (gnomAD).

What do computational predictors say about ABCA8 p.Leu728Pro (c.2183T>C)?

AlphaMissense predicts likely pathogenic (score 0.7283) — an in-silico prediction, not a clinical call.

ABCA8 p.Leu728Pro

c.2183T>C · VCV3525340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7283 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.2%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7283	likely pathogenic
REVEL	0.655	pathogenic-leaning
SaProt	LLR -14.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 0.98
Regional constraint	o/e 1.01	unconstrained · MANE · 74 kb · p 0.82 · regional, not allelic
Overall
CADD	25.7	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 0.2% Middle Eastern · 12/6,004 alleles

Filtering AF 0.115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0904%

Overall 0.00323% 52/1,608,182 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.2%	500
Remaining individualsnot grpmax-eligible	0.00964%	10,378
African / African-American	0.00669%	14,944
European (non-Finnish)	0.00229%	43,628
Admixed American	0.00169%	59,134
South Asian	0.00112%	89,078

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: ABCA8
Protein: p.Leu728Pro
Coding: c.2183T>C
MANE Select: NM_001288985
Type: single nucleotide variant
Location: chr17:68907835 (GRCh38)
Gene constraint: LOEUF 1.086 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.67

Full ABCA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA8 p.Gly176Ser Uncertain significance ★★ ⚠ same type
ABCA8 c.4200-1G>C Benign ★★ same type
ABCA8 p.Gly1225Glu Benign ★★ same type
ABCA8 p.Ile542= Benign/Likely benign ★★ same type
ABCA8 p.Met251Ile Benign ★★ same type
ABCA8 c.3316-8G>T Uncertain significance ★ same type
ABCA8 p.Ala1109Val Uncertain significance ★ ⚠ same type
ABCA8 p.Ala1344Ser 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/abca8-p-leu728pro (accessed [today's date]).

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