Is ABCD2 p.Arg684His (c.2051G>A) pathogenic?

ABCD2 p.Arg684His (c.2051G>A) is classified Uncertain significance in ABCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.0924); Ultra-rare (popmax 0.0855%, afr).

How common is ABCD2 p.Arg684His (c.2051G>A) in the general population?

ABCD2 p.Arg684His (c.2051G>A) is ultra-rare (popmax 0.0855%, afr) (gnomAD).

What do computational predictors say about ABCD2 p.Arg684His (c.2051G>A)?

AlphaMissense predicts likely benign (score 0.0924) — an in-silico prediction, not a clinical call.

ABCD2 p.Arg684His

c.2051G>A · rs779301167 · VCV3129098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0924 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0855%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0924	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -7.48	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 2.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 50 kb · p 0.028 · regional, not allelic
Overall
CADD	21.4	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 0.0855% African / African-American · 64/74,884 alleles

Filtering AF 0.0687% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0625%

Overall 0.00837% 135/1,613,448 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0855%	1,170
Remaining individualsnot grpmax-eligible	0.0064%	15,615
Admixed American	0.005%	19,983
European (non-Finnish)	0.005%	19,997
South Asian	0.00439%	22,767
Finnishnot grpmax-eligible	0.00156%	63,900

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.Arg684His
Coding: c.2051G>A
MANE Select: NM_005164
dbSNP: rs779301167
Type: single nucleotide variant
Location: chr12:39554084 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.65
Residue 684: 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-arg684his (accessed [today's date]).

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