Is ABCD2 p.Val457Ala (c.1370T>C) pathogenic?

ABCD2 p.Val457Ala (c.1370T>C) is classified Uncertain significance in ABCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-10). AlphaMissense: likely benign (0.0662); Very rare (popmax 0.00401%, afr).

How common is ABCD2 p.Val457Ala (c.1370T>C) in the general population?

ABCD2 p.Val457Ala (c.1370T>C) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about ABCD2 p.Val457Ala (c.1370T>C)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

ABCD2 p.Val457Ala

c.1370T>C · VCV3307093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.70	donor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.1	GERP -2
Regional constraint	o/e 0.65	unconstrained · MANE · 14 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	7.282	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,868 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000373% 6/1,610,388 alleles · very rare exomes 6/1,458,236 · genomes 0/152,152 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0047%	21,285
African / African-Americangrpmax	0.00401%	24,956

Finnish 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: ABCD2
Protein: p.Val457Ala
Coding: c.1370T>C
MANE Select: NM_005164
Type: single nucleotide variant
Location: chr12:39604797 (GRCh38)
Gene constraint: LOEUF 0.714 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.65

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-val457ala (accessed [today's date]).

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