Is ABCA8 p.Leu180Phe (c.538C>T) pathogenic?

ABCA8 p.Leu180Phe (c.538C>T) is classified Likely benign in ABCA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely benign (0.1355); Ultra-rare (popmax 0.0313%, eas).

How common is ABCA8 p.Leu180Phe (c.538C>T) in the general population?

ABCA8 p.Leu180Phe (c.538C>T) is ultra-rare (popmax 0.0313%, eas) (gnomAD).

What do computational predictors say about ABCA8 p.Leu180Phe (c.538C>T)?

AlphaMissense predicts likely benign (score 0.1355) — an in-silico prediction, not a clinical call.

ABCA8 p.Leu180Phe

c.538C>T · rs779473257 · VCV2596983

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1355 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0313%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1355	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	donor loss, 32 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.003	GERP -4.1, phastCons 0.001
Regional constraint	o/e 1.01	unconstrained · MANE · 74 kb · p 0.82 · regional, not allelic
Overall
CADD	10.21	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 0.0313% East Asian · 14/44,774 alleles

Filtering AF 0.0189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00105% 17/1,613,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0313%	3,198
African / African-American	0.00267%	37,495
Remaining individualsnot grpmax-eligible	0.0016%	62,458

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.Leu180Phe
Coding: c.538C>T
MANE Select: NM_001288985
dbSNP: rs779473257
Type: single nucleotide variant
Location: chr17:68933200 (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

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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-leu180phe (accessed [today's date]).

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