Is ABCA3 p.Arg43His (c.128G>A) pathogenic?

ABCA3 p.Arg43His (c.128G>A) is classified Pathogenic/Likely pathogenic in ABCA3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-06-15). AlphaMissense: likely pathogenic (0.6706); Very rare (popmax 0.00246%, nfe); Associated with Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies.

What condition is associated with ABCA3 p.Arg43His (c.128G>A)?

ABCA3 p.Arg43His (c.128G>A) is associated with Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies, hereditary pulmonary alveolar proteinosis, interstitial lung disease due to ABCA3 deficiency (ClinVar).

How common is ABCA3 p.Arg43His (c.128G>A) in the general population?

ABCA3 p.Arg43His (c.128G>A) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about ABCA3 p.Arg43His (c.128G>A)?

AlphaMissense predicts likely pathogenic (score 0.6706) — an in-silico prediction, not a clinical call.

ABCA3 p.Arg43His

c.128G>A · rs754714105 · VCV228321

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies

Computational evidence

Protein change
AlphaMissense	0.6706	likely pathogenic ✓ concordant with ClinVar
REVEL	0.95	strongly pathogenic-leaning
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 40 kb · p 0.47 · regional, not allelic
Overall
CADD	29.8	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 0.00246% European (non-Finnish) · 29/1,180,044 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00198% 32/1,613,970 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)grpmax	0.00246%	40,691
Admixed American	0.00167%	59,998
Remaining individualsnot grpmax-eligible	0.0016%	62,486

Ashkenazi Jewish 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.Arg43His
Coding: c.128G>A
MANE Select: NM_001089
dbSNP: rs754714105
Type: single nucleotide variant
Location: chr16:2326201 (GRCh38)
Gene constraint: LOEUF 0.612 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.00 · 2 PDB
Residue 43: a UniProt-annotated variant site (in smdp3; uncertain significance); an α-helix

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

Disease context

Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary pulmonary alveolar proteinosis interstitial lung disease due to ABCA3 deficiency

Similar variants

ABCA3 p.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ 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-arg43his (accessed [today's date]).

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