Is ABCA3 p.Phe478Leu (c.1432T>C) pathogenic?

ABCA3 p.Phe478Leu (c.1432T>C) is classified Uncertain significance in ABCA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-01). AlphaMissense: likely pathogenic (0.6982); Very rare (popmax 0.0061%, nfe); Associated with interstitial lung disease 2.

What condition is associated with ABCA3 p.Phe478Leu (c.1432T>C)?

ABCA3 p.Phe478Leu (c.1432T>C) is associated with interstitial lung disease 2, hereditary pulmonary alveolar proteinosis (ClinVar).

How common is ABCA3 p.Phe478Leu (c.1432T>C) in the general population?

ABCA3 p.Phe478Leu (c.1432T>C) is very rare (popmax 0.0061%, nfe) (gnomAD).

What do computational predictors say about ABCA3 p.Phe478Leu (c.1432T>C)?

AlphaMissense predicts likely pathogenic (score 0.6982) — an in-silico prediction, not a clinical call.

ABCA3 p.Phe478Leu

c.1432T>C · rs368903234 · VCV1705905

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0061%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

interstitial lung disease 2

Computational evidence

Protein change
AlphaMissense	0.6982	likely pathogenic
REVEL	0.434	indeterminate
SaProt	LLR -11.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 40 kb · p 0.47 · regional, not allelic
Overall
CADD	18.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0061% European (non-Finnish) · 72/1,180,026 alleles

Filtering AF 0.00495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00471% 76/1,614,058 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0061%	16,389
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed American	0.00167%	59,992

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.Phe478Leu
Coding: c.1432T>C
MANE Select: NM_001089
dbSNP: rs368903234
Type: single nucleotide variant
Location: chr16:2304004 (GRCh38)
Gene constraint: LOEUF 0.612 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.00 · 2 PDB
Residue 478: a β-strand

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

Disease context

interstitial lung disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary pulmonary alveolar proteinosis

Similar variants

ABCA3 p.Phe478= Likely benign ★★ same residue
ABCA3 c.2053-1G>C Likely pathogenic ★★ same condition
ABCA3 c.3863-98C>T Pathogenic ★★ same condition
ABCA3 p.Arg1550Trp Likely pathogenic ★★ same condition
ABCA3 p.Arg43Cys Pathogenic/Likely pathogenic ★★ same condition
ABCA3 p.Arg43His Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCA3 p.Glu1540Lys Likely pathogenic ★★ same condition
ABCA3 p.Glu292Val Pathogenic/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-phe478leu (accessed [today's date]).

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