Is SFTPC p.Val48Met (c.142G>A) pathogenic?

SFTPC p.Val48Met (c.142G>A) is classified Conflicting classifications of pathogenicity in SFTPC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-07). AlphaMissense: likely benign (0.3102); Ultra-rare (popmax 0.0134%, eas); Associated with surfactant metabolism dysfunction, pulmonary, 2.

What condition is associated with SFTPC p.Val48Met (c.142G>A)?

SFTPC p.Val48Met (c.142G>A) is associated with surfactant metabolism dysfunction, pulmonary, 2, hereditary pulmonary alveolar proteinosis, interstitial lung disease 2 (ClinVar).

How common is SFTPC p.Val48Met (c.142G>A) in the general population?

SFTPC p.Val48Met (c.142G>A) is ultra-rare (popmax 0.0134%, eas) (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.Val48Met (c.142G>A)?

AlphaMissense predicts likely benign (score 0.3102) — an in-silico prediction, not a clinical call.

SFTPC p.Val48Met

c.142G>A · rs566914013 · VCV362553

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3102 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

surfactant metabolism dysfunction, pulmonary, 2

Computational evidence

Protein change
AlphaMissense	0.3102	likely benign
REVEL	0.616	indeterminate
SaProt	LLR -6.22	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 8.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,209 bp · p 0.036 · regional, not allelic
Overall
CADD	26.2	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 0.0134% East Asian · 6/44,880 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00297% 48/1,614,222 alleles · ultra-rare exomes 46/1,461,886 · genomes 2/152,336 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,921
East Asiangrpmax	0.0134%	7,480
European (non-Finnish)	0.0022%	45,386

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: SFTPC
Protein: p.Val48Met
Coding: c.142G>A
MANE Select: NM_001317778
dbSNP: rs566914013
Type: single nucleotide variant
Location: chr8:22162673 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.71 · 3 PDB

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: hereditary pulmonary alveolar proteinosis 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.Val48= Likely benign ★ same residue
SFTPC c.435+2T>C Pathogenic/Likely pathogenic ★★ same condition
SFTPC p.Ile73Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
SFTPC p.Leu110Pro 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-val48met (accessed [today's date]).

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