Is ABCA3 p.Ile251= (c.753C>T) pathogenic?

ABCA3 p.Ile251= (c.753C>T) is classified Conflicting classifications of pathogenicity in ABCA3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-25). Rare (popmax 0.313%, mid); Associated with hereditary pulmonary alveolar proteinosis.

What condition is associated with ABCA3 p.Ile251= (c.753C>T)?

ABCA3 p.Ile251= (c.753C>T) is associated with hereditary pulmonary alveolar proteinosis, interstitial lung disease due to ABCA3 deficiency (ClinVar).

How common is ABCA3 p.Ile251= (c.753C>T) in the general population?

ABCA3 p.Ile251= (c.753C>T) is rare (popmax 0.313%, 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.Ile251=

c.753C>T · rs146161376 · VCV318568

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.313%, 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 0.14	GERP -3.5, phastCons 0.59
Overall
CADD	6.611	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.313% Middle Eastern · 19/6,062 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.171%

Overall 0.0309% 498/1,614,004 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.313%	319
Admixed American	0.2%	500
Remaining individualsnot grpmax-eligible	0.0672%	1,488
African / African-American	0.0267%	3,751
European (non-Finnish)	0.0242%	4,126
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867
East Asian	0.00891%	11,218
South Asian	0.00439%	22,769

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.Ile251=
Coding: c.753C>T
MANE Select: NM_001089
dbSNP: rs146161376
Type: single nucleotide variant
Location: chr16:2319701 (GRCh38)
Gene constraint: LOEUF 0.612 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.00 · 2 PDB

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 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
ABCA3 p.Arg155Trp 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-ile251 (accessed [today's date]).

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