Is ABCA3 p.Arg998= (c.2994C>T) pathogenic?

ABCA3 p.Arg998= (c.2994C>T) is classified Conflicting classifications of pathogenicity in ABCA3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-18). Ultra-rare (popmax 0.0687%, mid); Associated with hereditary pulmonary alveolar proteinosis.

What condition is associated with ABCA3 p.Arg998= (c.2994C>T)?

ABCA3 p.Arg998= (c.2994C>T) is associated with hereditary pulmonary alveolar proteinosis, interstitial lung disease due to ABCA3 deficiency (ClinVar).

How common is ABCA3 p.Arg998= (c.2994C>T) in the general population?

ABCA3 p.Arg998= (c.2994C>T) is ultra-rare (popmax 0.0687%, mid) (gnomAD).

How is Hereditary pulmonary alveolar proteinosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ABCA3 p.Arg998=

c.2994C>T · rs748766458 · VCV318430

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0687%, mid)

Conditions

hereditary pulmonary alveolar proteinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -4.8
Overall
CADD	0.144	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0687% Middle Eastern · 4/5,826 alleles

Filtering AF 0.0235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.014%

Overall 0.00317% 51/1,607,476 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0687%	1,457
Remaining individualsnot grpmax-eligible	0.00801%	12,480
Finnishnot grpmax-eligible	0.00345%	28,965
European (non-Finnish)	0.00331%	30,256
South Asian	0.0011%	91,062

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.Arg998=
Coding: c.2994C>T
MANE Select: NM_001089
dbSNP: rs748766458
Type: single nucleotide variant
Location: chr16:2288036 (GRCh38)
Gene constraint: LOEUF 0.612 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.00 · 2 PDB
Residue 998: a β-strand

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

Disease context

hereditary pulmonary alveolar proteinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: interstitial lung disease due to ABCA3 deficiency

For Hereditary pulmonary alveolar proteinosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly, Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

ABCA3 p.Arg998Cys 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
ABCA3 p.Arg1550Trp 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-arg998 (accessed [today's date]).

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