Is ABCD4 p.Phe464Leu (c.1392C>G) pathogenic?

ABCD4 p.Phe464Leu (c.1392C>G) is classified Uncertain significance in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). AlphaMissense: likely pathogenic (0.9538); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with ABCD4 p.Phe464Leu (c.1392C>G)?

ABCD4 p.Phe464Leu (c.1392C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ABCD4 p.Phe464Leu (c.1392C>G) in the general population?

ABCD4 p.Phe464Leu (c.1392C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ABCD4 p.Phe464Leu (c.1392C>G)?

AlphaMissense predicts likely pathogenic (score 0.9538) — an in-silico prediction, not a clinical call.

ABCD4 p.Phe464Leu

c.1392C>G · VCV3307661

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9538	likely pathogenic
REVEL	0.565	indeterminate
SaProt	LLR -8.47	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	23.9	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 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.000169%	590,023

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.Phe464Leu
Coding: c.1392C>G
MANE Select: NM_005050
Type: single nucleotide variant
Location: chr14:74290054 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 464: the abc transporter domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCD4 p.Arg127Cys Uncertain significance ★★ ⚠ same condition
ABCD4 p.Arg252Gly Uncertain significance ★★ ⚠ same condition
ABCD4 p.Arg391Gln Uncertain significance ★★ ⚠ same condition
ABCD4 p.Arg442Gln Uncertain significance ★★ ⚠ same condition
ABCD4 p.Gln215Arg Uncertain significance ★★ ⚠ same condition
ABCD4 p.Gln446Arg Uncertain significance ★★ ⚠ same condition
ABCD4 p.Gly566Ser Uncertain significance ★★ ⚠ same condition
ABCD4 p.Leu157Val Uncertain significance ★★ ⚠ same condition

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-phe464leu (accessed [today's date]).

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