Is ABCA3 p.Leu960Phe (c.2880G>C) pathogenic?

ABCA3 p.Leu960Phe (c.2880G>C) is classified Conflicting classifications of pathogenicity in ABCA3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-12). AlphaMissense: ambiguous (0.4014); Very rare (popmax 0.00433%, nfe); Associated with hereditary pulmonary alveolar proteinosis.

What condition is associated with ABCA3 p.Leu960Phe (c.2880G>C)?

ABCA3 p.Leu960Phe (c.2880G>C) is associated with hereditary pulmonary alveolar proteinosis, interstitial lung disease due to ABCA3 deficiency (ClinVar).

How common is ABCA3 p.Leu960Phe (c.2880G>C) in the general population?

ABCA3 p.Leu960Phe (c.2880G>C) is very rare (popmax 0.00433%, nfe) (gnomAD).

How is Hereditary pulmonary alveolar proteinosis inherited?

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

What do computational predictors say about ABCA3 p.Leu960Phe (c.2880G>C)?

AlphaMissense predicts ambiguous (score 0.4014) — an in-silico prediction, not a clinical call.

ABCA3 p.Leu960Phe

c.2880G>C · rs1022923684 · VCV932908

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4014 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00433%, nfe)

Conditions

hereditary pulmonary alveolar proteinosis

Computational evidence

Protein change
AlphaMissense	0.4014	ambiguous
REVEL	0.607	indeterminate
SaProt	LLR -4.05	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP 0.14, phastCons 0.28
Regional constraint	o/e 0.98	unconstrained · MANE · 40 kb · p 0.47 · regional, not allelic
Overall
CADD	18.42	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 0.00433% European (non-Finnish) · 51/1,178,884 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00363% 53/1,459,074 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00433%	23,115
Remaining individualsnot grpmax-eligible	0.0032%	31,210

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.Leu960Phe
Coding: c.2880G>C
MANE Select: NM_001089
dbSNP: rs1022923684
Type: single nucleotide variant
Location: chr16:2288150 (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 p.Leu960Ser Uncertain significance ★ ⚠ same residue
ABCA3 p.Leu960Val 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-leu960phe (accessed [today's date]).

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