Is SFTPC p.Pro14= (c.42G>A) pathogenic?

SFTPC p.Pro14= (c.42G>A) is classified Conflicting classifications of pathogenicity in SFTPC (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-10). Ultra-rare (popmax 0.0624%, nfe); Associated with interstitial lung disease 2.

What condition is associated with SFTPC p.Pro14= (c.42G>A)?

SFTPC p.Pro14= (c.42G>A) is associated with interstitial lung disease 2, hereditary pulmonary alveolar proteinosis, surfactant metabolism dysfunction, pulmonary, 2 (ClinVar).

How common is SFTPC p.Pro14= (c.42G>A) in the general population?

SFTPC p.Pro14= (c.42G>A) is ultra-rare (popmax 0.0624%, nfe) (gnomAD).

SFTPC p.Pro14=

c.42G>A · rs199905878 · VCV362551

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0624%, nfe)

Conditions

interstitial lung disease 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.45	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.56	GERP -2.2, phastCons 0.99
Overall
CADD	18.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0624% European (non-Finnish) · 736/1,179,980 alleles

Filtering AF 0.0586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0571%

Overall 0.0612% 988/1,613,964 alleles · ultra-rare exomes 900/1,461,646 · genomes 88/152,318 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.658%	152
Finnishnot grpmax-eligible	0.194%	515
Remaining individualsnot grpmax-eligible	0.0784%	1,276
European (non-Finnish)grpmax	0.0624%	1,603
South Asian	0.056%	1,786
Middle Eastern	0.0495%	2,021
African / African-American	0.0173%	5,773
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
Admixed American	0.00666%	15,009

Amish 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.Pro14=
Coding: c.42G>A
MANE Select: NM_001317778
dbSNP: rs199905878
Type: single nucleotide variant
Location: chr8:22161870 (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

interstitial lung disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary pulmonary alveolar proteinosis surfactant metabolism dysfunction, pulmonary, 2

Similar variants

SFTPC p.Pro14Leu Uncertain significance ★ ⚠ 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-pro14 (accessed [today's date]).

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