Is ABCD2 p.Met617Ile (c.1851G>A) pathogenic?

ABCD2 p.Met617Ile (c.1851G>A) is classified Uncertain significance in ABCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.3953); Ultra-rare (popmax 0.0429%, sas).

How common is ABCD2 p.Met617Ile (c.1851G>A) in the general population?

ABCD2 p.Met617Ile (c.1851G>A) is ultra-rare (popmax 0.0429%, sas) (gnomAD).

What do computational predictors say about ABCD2 p.Met617Ile (c.1851G>A)?

AlphaMissense predicts ambiguous (score 0.3953) — an in-silico prediction, not a clinical call.

ABCD2 p.Met617Ile

c.1851G>A · VCV4136708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3953 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0429%, sas)

Computational evidence

Protein change
AlphaMissense	0.3953	ambiguous
REVEL	0.473	indeterminate
SaProt	LLR -8.62	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 50 kb · p 0.028 · regional, not allelic
Overall
CADD	20.9	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 0.0429% South Asian · 39/90,978 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0285%

Overall 0.00248% 40/1,613,170 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0429%	2,333
Remaining individualsnot grpmax-eligible	0.0016%	62,464

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: ABCD2
Protein: p.Met617Ile
Coding: c.1851G>A
MANE Select: NM_005164
Type: single nucleotide variant
Location: chr12:39579561 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.65
Residue 617: the abc transporter domain

Full ABCD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCD2 c.1878-18G>C Benign/Likely benign ★★ same type
ABCD2 p.Ala251Gly Uncertain significance ★ ⚠ same type
ABCD2 p.Ala273Thr Uncertain significance ★ ⚠ same type
ABCD2 p.Ala489Glu Uncertain significance ★ ⚠ same type
ABCD2 p.Arg16Thr Uncertain significance ★ ⚠ same type
ABCD2 p.Arg178Cys Uncertain significance ★ ⚠ same type
ABCD2 p.Arg178His Uncertain significance ★ ⚠ same type
ABCD2 p.Arg337Cys 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/abcd2-p-met617ile (accessed [today's date]).

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