Is ABCA8 p.Glu111Asp (c.333A>C) pathogenic?

ABCA8 p.Glu111Asp (c.333A>C) is classified Uncertain significance in ABCA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-14). AlphaMissense: likely benign (0.1189); Very rare (popmax 0.00637%, nfe).

How common is ABCA8 p.Glu111Asp (c.333A>C) in the general population?

ABCA8 p.Glu111Asp (c.333A>C) is very rare (popmax 0.00637%, nfe) (gnomAD).

What do computational predictors say about ABCA8 p.Glu111Asp (c.333A>C)?

AlphaMissense predicts likely benign (score 0.1189) — an in-silico prediction, not a clinical call.

ABCA8 p.Glu111Asp

c.333A>C · VCV3858460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1189 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00637%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1189	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -6.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -2.1
Regional constraint	o/e 1.01	unconstrained · MANE · 74 kb · p 0.82 · regional, not allelic
Overall
CADD	5.477	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00637% European (non-Finnish) · 75/1,178,096 alleles

Filtering AF 0.0052% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00497% 80/1,608,970 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00637%	15,708
Remaining individualsnot grpmax-eligible	0.00482%	20,751
Finnishnot grpmax-eligible	0.00157%	63,862
African / African-American	0.00134%	74,604

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.Glu111Asp
Coding: c.333A>C
MANE Select: NM_001288985
Type: single nucleotide variant
Location: chr17:68937084 (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-glu111asp (accessed [today's date]).

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