Is ABCA3 p.Pro249Leu (c.746C>T) pathogenic?

ABCA3 p.Pro249Leu (c.746C>T) is classified Likely pathogenic in ABCA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-24). AlphaMissense: likely benign (0.3091); Very rare (popmax 0.00892%, eas); Associated with interstitial lung disease due to ABCA3 deficiency.

What condition is associated with ABCA3 p.Pro249Leu (c.746C>T)?

ABCA3 p.Pro249Leu (c.746C>T) is associated with interstitial lung disease due to ABCA3 deficiency (ClinVar).

How common is ABCA3 p.Pro249Leu (c.746C>T) in the general population?

ABCA3 p.Pro249Leu (c.746C>T) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about ABCA3 p.Pro249Leu (c.746C>T)?

AlphaMissense predicts likely benign (score 0.3091) — an in-silico prediction, not a clinical call.

ABCA3 p.Pro249Leu

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.746C>T · VCV3580037

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

interstitial lung disease due to ABCA3 deficiency

Computational evidence

Protein change
AlphaMissense	0.3091	likely benign ⚠ discordant with ClinVar
REVEL	0.58	indeterminate
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 40 kb · p 0.47 · regional, not allelic
Overall
CADD	23.3	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 0.00892% East Asian · 4/44,866 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00281% 41/1,461,586 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,216
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00288%	34,706
Admixed American	0.00167%	59,994
South Asian	0.0011%	91,082

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.Pro249Leu
Coding: c.746C>T
MANE Select: NM_001089
Type: single nucleotide variant
Location: chr16:2319708 (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

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

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

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ABCA3 p.Pro249= Conflicting classifications of pathogenicity ★ same residue
ABCA3 c.1112-20G>A 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-pro249leu (accessed [today's date]).

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