Is SFTPC p.Ala149Pro (c.445G>C) pathogenic?

SFTPC p.Ala149Pro (c.445G>C) is classified Conflicting classifications of pathogenicity in SFTPC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-11-21). AlphaMissense: likely benign (0.0991); Ultra-rare (popmax 0.0274%, sas); Associated with surfactant metabolism dysfunction, pulmonary, 2.

What condition is associated with SFTPC p.Ala149Pro (c.445G>C)?

SFTPC p.Ala149Pro (c.445G>C) is associated with surfactant metabolism dysfunction, pulmonary, 2, interstitial lung disease 2 (ClinVar).

How common is SFTPC p.Ala149Pro (c.445G>C) in the general population?

SFTPC p.Ala149Pro (c.445G>C) is ultra-rare (popmax 0.0274%, sas) (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 SFTPC p.Ala149Pro (c.445G>C)?

AlphaMissense predicts likely benign (score 0.0991) — an in-silico prediction, not a clinical call.

SFTPC p.Ala149Pro

c.445G>C · rs202145169 · VCV362560

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0991 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0274%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

surfactant metabolism dysfunction, pulmonary, 2

Computational evidence

Protein change
AlphaMissense	0.0991	likely benign
REVEL	0.547	indeterminate
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.9, phastCons 0.002
Regional constraint	o/e 0.87	unconstrained · MANE · 2,209 bp · p 0.036 · regional, not allelic
Overall
CADD	11.75	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A155P vs ClinVar A149P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0274% South Asian · 25/91,086 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0163%

Overall 0.0159% 256/1,613,812 alleles · ultra-rare exomes 236/1,461,432 · genomes 20/152,380 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0274%	3,643
European (non-Finnish)	0.0182%	5,488
Middle Eastern	0.0166%	6,034
Remaining individualsnot grpmax-eligible	0.016%	6,250
Admixed American	0.00666%	15,009
African / African-American	0.00133%	75,068

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: SFTPC
Protein: p.Ala149Pro
Coding: c.445G>C
MANE Select: NM_001317778
dbSNP: rs202145169
Type: single nucleotide variant
Location: chr8:22163910 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.71 · 3 PDB
Residue 155 UniProt numbering: a β-strand; the brichos domain

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

Disease context

surfactant metabolism dysfunction, pulmonary, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: interstitial lung disease 2

For Hereditary pulmonary alveolar proteinosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly, Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

SFTPC p.Ala149Ser Uncertain significance ★ ⚠ same residue
SFTPC p.Ala149fs Likely pathogenic ★ same residue
SFTPC c.435+2T>C Pathogenic/Likely pathogenic ★★ same condition
SFTPC p.Ile73Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
SFTPC c.*193C>A Uncertain significance ★★ same condition
SFTPC p.Ile50Met Uncertain significance ★★ ⚠ same condition
SFTPC p.Leu45Pro Uncertain significance ★★ ⚠ same condition
SFTPC p.Val39Met Uncertain significance ★★ ⚠ 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/sftpc-p-ala149pro (accessed [today's date]).

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