Is ABCD3 p.Val616Ile (c.1846G>A) pathogenic?

ABCD3 p.Val616Ile (c.1846G>A) is classified Uncertain significance in ABCD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.1456); Very rare (popmax 0.00448%, eas).

How common is ABCD3 p.Val616Ile (c.1846G>A) in the general population?

ABCD3 p.Val616Ile (c.1846G>A) is very rare (popmax 0.00448%, eas) (gnomAD).

What do computational predictors say about ABCD3 p.Val616Ile (c.1846G>A)?

AlphaMissense predicts likely benign (score 0.1456) — an in-silico prediction, not a clinical call.

ABCD3 p.Val616Ile

c.1846G>A · VCV4138461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1456 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00448%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1456	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -6.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.48 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 29 kb · p 0.00033 · regional, not allelic
Overall
CADD	29.8	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 0.00448% East Asian · 2/44,648 alleles

Filtering AF 0.000742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000137% 2/1,455,360 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: ABCD3
Protein: p.Val616Ile
Coding: c.1846G>A
MANE Select: NM_002858
Type: single nucleotide variant
Location: chr1:94515146 (GRCh38)
Gene constraint: LOEUF 0.484 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 83.39 · 9 PDB
Residue 616: the abc transporter domain; an α-helix

Full ABCD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ABCD3 p.Arg496Cys Uncertain significance ★★ ⚠ same type
ABCD3 p.Asn12Tyr Uncertain significance ★★ ⚠ same type
ABCD3 p.Ile225Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Leu23Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Leu45Val Uncertain significance ★★ ⚠ same type
ABCD3 p.Pro425Leu 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/abcd3-p-val616ile (accessed [today's date]).

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