Is ABCD4 p.Pro526Leu (c.1577C>T) pathogenic?

ABCD4 p.Pro526Leu (c.1577C>T) is classified Uncertain significance in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-12). AlphaMissense: ambiguous (0.5486); Very rare (popmax 0.00153%, nfe).

How common is ABCD4 p.Pro526Leu (c.1577C>T) in the general population?

ABCD4 p.Pro526Leu (c.1577C>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about ABCD4 p.Pro526Leu (c.1577C>T)?

AlphaMissense predicts ambiguous (score 0.5486) — an in-silico prediction, not a clinical call.

ABCD4 p.Pro526Leu

c.1577C>T · rs534596852 · VCV1306509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5486 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5486	ambiguous
REVEL	0.822	moderately pathogenic-leaning
SaProt	LLR -8.36	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, 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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,179,482 alleles

Filtering AF 0.000954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.0024% 35/1,460,706 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,958
Remaining individualsnot grpmax-eligible	0.008%	12,493
European (non-Finnish)grpmax	0.00153%	65,527
African / African-American	0.00133%	75,022
South Asian	0.0011%	90,850

Ashkenazi Jewish 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: ABCD4
Protein: p.Pro526Leu
Coding: c.1577C>T
MANE Select: NM_005050
dbSNP: rs534596852
Type: single nucleotide variant
Location: chr14:74287869 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18 · 4 PDB
Residue 526: the abc transporter domain

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

Similar variants

ABCD4 p.Pro526= Likely benign ★ 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
ABCD4 c.1028+5G>A Uncertain significance ★★ same type
ABCD4 c.425+6C>T 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-pro526leu (accessed [today's date]).

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