Is ABCA8 p.Met404Ile (c.1212G>C) pathogenic?

ABCA8 p.Met404Ile (c.1212G>C) is classified Uncertain significance in ABCA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: ambiguous (0.4404); Very rare (popmax 0.00034%, nfe).

How common is ABCA8 p.Met404Ile (c.1212G>C) in the general population?

ABCA8 p.Met404Ile (c.1212G>C) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about ABCA8 p.Met404Ile (c.1212G>C)?

AlphaMissense predicts ambiguous (score 0.4404) — an in-silico prediction, not a clinical call.

ABCA8 p.Met404Ile

c.1212G>C · VCV4090602

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4404 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4404	ambiguous
REVEL	0.313	indeterminate
SaProt	LLR -7.36	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP 0.88, phastCons 0.008
Regional constraint	o/e 1.01	unconstrained · MANE · 74 kb · p 0.82 · regional, not allelic
Overall
CADD	6.778	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 0.00034% European (non-Finnish) · 4/1,178,100 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000275% 4/1,456,164 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.Met404Ile
Coding: c.1212G>C
MANE Select: NM_001288985
Type: single nucleotide variant
Location: chr17:68927977 (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.Met404Leu Uncertain significance ★ ⚠ same residue
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

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-met404ile (accessed [today's date]).

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