Is ABCA8 p.Leu765Phe (c.2293C>T) pathogenic?

ABCA8 p.Leu765Phe (c.2293C>T) is classified Uncertain significance in ABCA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.2063); Very rare (popmax 0.0006%, nfe).

How common is ABCA8 p.Leu765Phe (c.2293C>T) in the general population?

ABCA8 p.Leu765Phe (c.2293C>T) is very rare (popmax 0.0006%, nfe) (gnomAD).

What do computational predictors say about ABCA8 p.Leu765Phe (c.2293C>T)?

AlphaMissense predicts likely benign (score 0.2063) — an in-silico prediction, not a clinical call.

ABCA8 p.Leu765Phe

c.2293C>T · VCV4090280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0006%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2063	likely benign
REVEL	0.676	pathogenic-leaning
SaProt	LLR -8.26	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 74 kb · p 0.82 · regional, not allelic
Overall
CADD	24.3	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 0.0006% European (non-Finnish) · 7/1,166,466 alleles

Filtering AF 0.00025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000161%

Overall 0.000443% 7/1,581,348 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: ABCA8
Protein: p.Leu765Phe
Coding: c.2293C>T
MANE Select: NM_001288985
Type: single nucleotide variant
Location: chr17:68906149 (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-leu765phe (accessed [today's date]).

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