Is ABCD4 p.Ala545Ser (c.1633G>T) pathogenic?

ABCD4 p.Ala545Ser (c.1633G>T) is classified Uncertain significance in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-16). AlphaMissense: ambiguous (0.4767); Very rare (popmax 0.00894%, eas); Associated with Inborn genetic diseases.

What condition is associated with ABCD4 p.Ala545Ser (c.1633G>T)?

ABCD4 p.Ala545Ser (c.1633G>T) is associated with Inborn genetic diseases (ClinVar).

How common is ABCD4 p.Ala545Ser (c.1633G>T) in the general population?

ABCD4 p.Ala545Ser (c.1633G>T) is very rare (popmax 0.00894%, eas) (gnomAD).

What do computational predictors say about ABCD4 p.Ala545Ser (c.1633G>T)?

AlphaMissense predicts ambiguous (score 0.4767) — an in-silico prediction, not a clinical call.

ABCD4 p.Ala545Ser

c.1633G>T · rs754370477 · VCV2289890

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4767 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00894%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4767	ambiguous
REVEL	0.819	moderately pathogenic-leaning
SaProt	LLR -10.88	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.25	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.7	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 0.00894% East Asian · 4/44,740 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00031% 5/1,610,916 alleles · very rare exomes 4/1,458,708 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00894%	11,185
Admixed American	0.00167%	59,702

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.Ala545Ser
Coding: c.1633G>T
MANE Select: NM_005050
dbSNP: rs754370477
Type: single nucleotide variant
Location: chr14:74287813 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 545: 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.Ala545Thr Uncertain significance ★★ ⚠ same residue
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

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-ala545ser (accessed [today's date]).

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