Is ABCA9 p.Trp108Arg (c.322T>C) pathogenic?

ABCA9 p.Trp108Arg (c.322T>C) is classified Uncertain significance in ABCA9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: ambiguous (0.4465); Very rare (popmax 0.00669%, afr).

How common is ABCA9 p.Trp108Arg (c.322T>C) in the general population?

ABCA9 p.Trp108Arg (c.322T>C) is very rare (popmax 0.00669%, afr) (gnomAD).

What do computational predictors say about ABCA9 p.Trp108Arg (c.322T>C)?

AlphaMissense predicts ambiguous (score 0.4465) — an in-silico prediction, not a clinical call.

ABCA9 p.Trp108Arg

c.322T>C · VCV4636038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4465 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4465	ambiguous
REVEL	0.279	benign-leaning
SaProt	LLR -2.15	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.6	GERP -3.5
Regional constraint	o/e 0.94	unconstrained · MANE · 75 kb · p 0.014 · regional, not allelic
Overall
CADD	7.08	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 0.00669% African / African-American · 5/74,686 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000343% 5/1,458,868 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: ABCA9
Protein: p.Trp108Arg
Coding: c.322T>C
MANE Select: NM_080283
Type: single nucleotide variant
Location: chr17:69045319 (GRCh38)
Gene constraint: LOEUF 1.006 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.22

Full ABCA9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA9 p.Tyr1123= Likely benign ★★ same type
ABCA9 p.Ala1071Val Uncertain significance ★ ⚠ same type
ABCA9 p.Ala1153Thr Uncertain significance ★ ⚠ same type
ABCA9 p.Ala1196Thr Uncertain significance ★ ⚠ same type
ABCA9 p.Ala125Thr Uncertain significance ★ ⚠ same type
ABCA9 p.Ala1285Thr Uncertain significance ★ ⚠ same type
ABCA9 p.Ala1407Val Uncertain significance ★ ⚠ same type
ABCA9 p.Ala1492Pro 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/abca9-p-trp108arg (accessed [today's date]).

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