Is ABCD3 p.Arg335His (c.1004G>A) pathogenic?

ABCD3 p.Arg335His (c.1004G>A) is classified Uncertain significance in ABCD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-23). AlphaMissense: likely benign (0.2184); Very rare (popmax 0.00136%, nfe).

How common is ABCD3 p.Arg335His (c.1004G>A) in the general population?

ABCD3 p.Arg335His (c.1004G>A) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about ABCD3 p.Arg335His (c.1004G>A)?

AlphaMissense predicts likely benign (score 0.2184) — an in-silico prediction, not a clinical call.

ABCD3 p.Arg335His

c.1004G>A · rs778909026 · VCV1989394

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2184 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2184	likely benign
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -11.37	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP 0.14, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 23 kb · p 3.7e-09 · regional, not allelic
Overall
CADD	26.6	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 0.00136% European (non-Finnish) · 16/1,179,926 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00112% 18/1,613,786 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)grpmax	0.00136%	73,745
African / African-American	0.00134%	74,870

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ABCD3
Protein: p.Arg335His
Coding: c.1004G>A
MANE Select: NM_002858
dbSNP: rs778909026
Type: single nucleotide variant
Location: chr1:94487730 (GRCh38)
Gene constraint: LOEUF 0.484 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 83.39 · 9 PDB
Residue 335: the abc transmembrane type-1 domain; a turn

Full ABCD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ABCD3 p.Asn12Tyr Uncertain significance ★★ ⚠ same type
ABCD3 p.Ile225Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Leu23Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Leu45Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Pro425Leu 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/abcd3-p-arg335his (accessed [today's date]).

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