Is ABCA3 p.Arg395Trp (c.1183C>T) pathogenic?

ABCA3 p.Arg395Trp (c.1183C>T) is classified Uncertain significance in ABCA3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-11). AlphaMissense: likely benign (0.2242); Very rare (popmax 0.00891%, eas); Associated with interstitial lung disease due to ABCA3 deficiency.

What condition is associated with ABCA3 p.Arg395Trp (c.1183C>T)?

ABCA3 p.Arg395Trp (c.1183C>T) is associated with interstitial lung disease due to ABCA3 deficiency, hereditary pulmonary alveolar proteinosis (ClinVar).

How common is ABCA3 p.Arg395Trp (c.1183C>T) in the general population?

ABCA3 p.Arg395Trp (c.1183C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about ABCA3 p.Arg395Trp (c.1183C>T)?

AlphaMissense predicts likely benign (score 0.2242) — an in-silico prediction, not a clinical call.

ABCA3 p.Arg395Trp

Q: How is Interstitial lung disease due to ABCA3 deficiency inherited?

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

c.1183C>T · rs201681616 · VCV318558

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2242 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

interstitial lung disease due to ABCA3 deficiency

Computational evidence

Protein change
AlphaMissense	0.2242	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.5	GERP -2.2, phastCons 0.96
Regional constraint	o/e 0.98	unconstrained · MANE · 40 kb · p 0.47 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00891% East Asian · 4/44,900 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00514% 83/1,614,086 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,249
East Asiangrpmax	0.00891%	11,225
Finnishnot grpmax-eligible	0.00781%	12,807
European (non-Finnish)	0.00517%	19,345
South Asian	0.0022%	45,542
African / African-American	0.00133%	74,944

Remaining individuals 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.Arg395Trp
Coding: c.1183C>T
MANE Select: NM_001089
dbSNP: rs201681616
Type: single nucleotide variant
Location: chr16:2308552 (GRCh38)
Gene constraint: LOEUF 0.612 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.00 · 2 PDB
Residue 395: an α-helix

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

Disease context

interstitial lung disease due to ABCA3 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary pulmonary alveolar proteinosis

For Interstitial lung disease due to ABCA3 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ABCA3 p.Arg395Gln Uncertain significance ★ ⚠ same residue
ABCA3 p.Arg395= Likely benign ★ 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-arg395trp (accessed [today's date]).

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