Is ABCA3 p.Arg280Cys (c.838C>T) pathogenic?

ABCA3 p.Arg280Cys (c.838C>T) is classified Conflicting classifications of pathogenicity in ABCA3 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-05-04). AlphaMissense: likely benign (0.3237); Ultra-rare (popmax 0.0417%, amr); Associated with ABCA3-related disorder.

What condition is associated with ABCA3 p.Arg280Cys (c.838C>T)?

ABCA3 p.Arg280Cys (c.838C>T) is associated with ABCA3-related disorder, hereditary pulmonary alveolar proteinosis, interstitial lung disease due to ABCA3 deficiency (ClinVar).

How common is ABCA3 p.Arg280Cys (c.838C>T) in the general population?

ABCA3 p.Arg280Cys (c.838C>T) is ultra-rare (popmax 0.0417%, amr) (gnomAD).

What do computational predictors say about ABCA3 p.Arg280Cys (c.838C>T)?

AlphaMissense predicts likely benign (score 0.3237) — an in-silico prediction, not a clinical call.

ABCA3 p.Arg280Cys

c.838C>T · rs201299260 · VCV318566

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.3237 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA3-related disorder

Computational evidence

Protein change
AlphaMissense	0.3237	likely benign
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -11.93	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.42, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 40 kb · p 0.47 · regional, not allelic
Overall
CADD	24.7	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 0.0417% Admixed American · 25/59,978 alleles

Filtering AF 0.0289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.0226% 364/1,613,144 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0417%	2,399
European (non-Finnish)	0.0272%	3,676
Remaining individualsnot grpmax-eligible	0.0192%	5,207
African / African-American	0.00668%	14,981
South Asian	0.0011%	91,078

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: ABCA3
Protein: p.Arg280Cys
Coding: c.838C>T
MANE Select: NM_001089
dbSNP: rs201299260
Type: single nucleotide variant
Location: chr16:2319616 (GRCh38)
Gene constraint: LOEUF 0.612 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.00 · 2 PDB
Residue 280: a UniProt-annotated variant site (in smdp3; uncertain significance; does not affect protein oligomerization); an α-helix

Full ABCA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ABCA3-related disorder

Also linked: hereditary pulmonary alveolar proteinosis interstitial lung disease due to ABCA3 deficiency

Similar variants

ABCA3 p.Arg280His Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCA3 p.Arg280Pro Uncertain significance ★ ⚠ same residue
ABCA3 c.1112-20G>A Likely pathogenic ★★ same condition
ABCA3 c.2053-1G>C Likely pathogenic ★★ same condition
ABCA3 c.2414+1G>A Likely pathogenic ★★ same condition
ABCA3 c.3863-98C>T Pathogenic ★★ same condition
ABCA3 c.614-2A>G Likely pathogenic ★★ same condition
ABCA3 p.Ala1070Thr Likely pathogenic ★★ ⚠ same condition

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/abca3-p-arg280cys (accessed [today's date]).

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