Is ABCA3 p.Arg280His (c.839G>A) pathogenic?

ABCA3 p.Arg280His (c.839G>A) is classified Conflicting classifications of pathogenicity in ABCA3 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.1791); Ultra-rare (popmax 0.095%, amr); Associated with Bullous lung disease.

What condition is associated with ABCA3 p.Arg280His (c.839G>A)?

ABCA3 p.Arg280His (c.839G>A) is associated with Bullous lung disease, hereditary pulmonary alveolar proteinosis, interstitial lung disease due to ABCA3 deficiency (ClinVar).

How common is ABCA3 p.Arg280His (c.839G>A) in the general population?

ABCA3 p.Arg280His (c.839G>A) is ultra-rare (popmax 0.095%, amr) (gnomAD).

What do computational predictors say about ABCA3 p.Arg280His (c.839G>A)?

AlphaMissense predicts likely benign (score 0.1791) — an in-silico prediction, not a clinical call.

ABCA3 p.Arg280His

c.839G>A · rs143008553 · VCV228421

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1791 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.095%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bullous lung disease

Computational evidence

Protein change
AlphaMissense	0.1791	likely benign
REVEL	0.62	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.48, phastCons 0.52
Regional constraint	o/e 0.98	unconstrained · MANE · 40 kb · p 0.47 · regional, not allelic
Overall
CADD	23.9	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 0.095% Admixed American · 57/60,000 alleles

Filtering AF 0.0872% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0854%

Overall 0.0862% 1,391/1,613,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	3.96%	25
Finnishnot grpmax-eligible	0.204%	489
Admixed Americangrpmax	0.095%	1,053
European (non-Finnish)	0.0918%	1,090
Remaining individualsnot grpmax-eligible	0.0672%	1,488
African / African-American	0.0507%	1,974
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,800
South Asian	0.00439%	22,771

Amish 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: ABCA3
Protein: p.Arg280His
Coding: c.839G>A
MANE Select: NM_001089
dbSNP: rs143008553
Type: single nucleotide variant
Location: chr16:2319615 (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

Bullous lung disease

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

Similar variants

ABCA3 p.Arg280Cys 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-arg280his (accessed [today's date]).

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