Is ABCD4 p.Arg145His (c.434G>A) pathogenic?

ABCD4 p.Arg145His (c.434G>A) is classified Uncertain significance in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-05). AlphaMissense: likely pathogenic (0.9196); Ultra-rare (popmax 0.0987%, mid).

How common is ABCD4 p.Arg145His (c.434G>A) in the general population?

ABCD4 p.Arg145His (c.434G>A) is ultra-rare (popmax 0.0987%, mid) (gnomAD).

What do computational predictors say about ABCD4 p.Arg145His (c.434G>A)?

AlphaMissense predicts likely pathogenic (score 0.9196) — an in-silico prediction, not a clinical call.

ABCD4 p.Arg145His

c.434G>A · VCV4922342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9196 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0987%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9196	likely pathogenic
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -12.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0987% Middle Eastern · 6/6,078 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.00161% 26/1,613,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0987%	1,013
African / African-American	0.016%	6,239
Admixed American	0.00333%	29,991
Remaining individualsnot grpmax-eligible	0.0032%	31,237
South Asian	0.0011%	91,084
European (non-Finnish)	0.000254%	393,331

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: ABCD4
Protein: p.Arg145His
Coding: c.434G>A
MANE Select: NM_005050
Type: single nucleotide variant
Location: chr14:74296441 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 145: the abc transmembrane type-1 domain

Full ABCD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCD4 p.Arg145Cys Uncertain significance ★ ⚠ same residue
ABCD4 p.Arg145Gly Uncertain significance ★ ⚠ same residue
ABCD4 p.Arg145Leu Uncertain significance ★ ⚠ same residue
ABCD4 c.542+1G>T Pathogenic ★★ same type
ABCD4 p.Arg432Gln Likely pathogenic ★★ same type
ABCD4 p.Asn141Lys Pathogenic/Likely pathogenic ★★ same type
ABCD4 p.Gln530Ter Pathogenic/Likely pathogenic ★★ same type
ABCD4 p.Tyr176Ter Pathogenic/Likely pathogenic ★★ 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/abcd4-p-arg145his (accessed [today's date]).

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