Is ABCD4 p.Gly414Arg (c.1240G>A) pathogenic?

ABCD4 p.Gly414Arg (c.1240G>A) is classified Uncertain significance in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-25). AlphaMissense: likely benign (0.3098); Very rare (popmax 0.000339%, nfe).

How common is ABCD4 p.Gly414Arg (c.1240G>A) in the general population?

ABCD4 p.Gly414Arg (c.1240G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ABCD4 p.Gly414Arg (c.1240G>A)?

AlphaMissense predicts likely benign (score 0.3098) — an in-silico prediction, not a clinical call.

ABCD4 p.Gly414Arg

c.1240G>A · VCV3361947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3098 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3098	likely benign
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -7.91	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	27.5	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 0.000339% European (non-Finnish) · 4/1,180,026 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,888 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: ABCD4
Protein: p.Gly414Arg
Coding: c.1240G>A
MANE Select: NM_005050
Type: single nucleotide variant
Location: chr14:74290378 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 414: the abc transporter domain

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

Similar variants

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
ABCD4 c.1028+5G>A Uncertain significance ★★ same type
ABCD4 c.425+6C>T Uncertain significance ★★ same type
ABCD4 c.719+6T>C 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/abcd4-p-gly414arg (accessed [today's date]).

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