Is ABCD2 p.Ile641Thr (c.1922T>C) pathogenic?

ABCD2 p.Ile641Thr (c.1922T>C) is classified Uncertain significance in ABCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: ambiguous (0.5384); Very rare (popmax 0.00223%, eas).

How common is ABCD2 p.Ile641Thr (c.1922T>C) in the general population?

ABCD2 p.Ile641Thr (c.1922T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ABCD2 p.Ile641Thr (c.1922T>C)?

AlphaMissense predicts ambiguous (score 0.5384) — an in-silico prediction, not a clinical call.

ABCD2 p.Ile641Thr

c.1922T>C · VCV3881219

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5384 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5384	ambiguous
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -7.59	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 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 50 kb · p 0.028 · regional, not allelic
Overall
CADD	27.1	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 0.00223% East Asian · 1/44,828 alleles

Overall 0.000205% 3/1,460,948 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,828
Admixed American	0.00167%	60,012
South Asian	0.0011%	91,050

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: ABCD2
Protein: p.Ile641Thr
Coding: c.1922T>C
MANE Select: NM_005164
Type: single nucleotide variant
Location: chr12:39573797 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.65
Residue 641: the abc transporter domain

Full ABCD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCD2 c.1878-18G>C Benign/Likely benign ★★ same type
ABCD2 p.Ala251Gly Uncertain significance ★ ⚠ same type
ABCD2 p.Ala273Thr Uncertain significance ★ ⚠ same type
ABCD2 p.Ala489Glu Uncertain significance ★ ⚠ same type
ABCD2 p.Arg16Thr Uncertain significance ★ ⚠ same type
ABCD2 p.Arg178Cys Uncertain significance ★ ⚠ same type
ABCD2 p.Arg178His Uncertain significance ★ ⚠ same type
ABCD2 p.Arg337Cys 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/abcd2-p-ile641thr (accessed [today's date]).

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