Is ABCD1 p.Ala646Val (c.1937C>T) pathogenic?

ABCD1 p.Ala646Val (c.1937C>T) is classified Uncertain significance in ABCD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-07). AlphaMissense: likely benign (0.2014); Very rare (popmax 0.000562%, nfe).

How common is ABCD1 p.Ala646Val (c.1937C>T) in the general population?

ABCD1 p.Ala646Val (c.1937C>T) is very rare (popmax 0.000562%, nfe) (gnomAD).

What do computational predictors say about ABCD1 p.Ala646Val (c.1937C>T)?

AlphaMissense predicts likely benign (score 0.2014) — an in-silico prediction, not a clinical call.

ABCD1 p.Ala646Val

c.1937C>T · rs1258368672 · VCV1693328

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2014 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000562%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2014	likely benign
REVEL	0.725	pathogenic-leaning
SaProt	LLR -8.55	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 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 3,261 bp · p 4e-11 · regional, not allelic
Overall
CADD	23.7	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 0.000562% European (non-Finnish) · 5/890,043 alleles

Filtering AF 0.000165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000417% 5/1,198,793 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: ABCD1
Protein: p.Ala646Val
Coding: c.1937C>T
MANE Select: NM_000033
dbSNP: rs1258368672
Type: single nucleotide variant
Location: chrX:153743292 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 646: a UniProt-annotated variant site (in ald); an α-helix; the abc transporter domain

Full ABCD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCD1 p.Ala646= Likely benign ★★ same residue
ABCD1 p.Ala646Ser Uncertain significance ★ ⚠ same residue
ABCD1 c.1635-2A>G Pathogenic ★★ same type
ABCD1 c.1781-1G>C Pathogenic ★★ same type
ABCD1 c.1781-1G>T Pathogenic/Likely pathogenic ★★ same type
ABCD1 c.1866-10G>A Pathogenic/Likely pathogenic ★★ same type
ABCD1 c.1866-1G>C Likely pathogenic ★★ same type
ABCD1 c.1866-2A>T Likely pathogenic ★★ 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/abcd1-p-ala646val (accessed [today's date]).

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