Is SFTPC p.Thr65= (c.195G>A) pathogenic?

SFTPC p.Thr65= (c.195G>A) is classified Likely benign in SFTPC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-30). Ultra-rare (popmax 0.0117%, amr); Associated with hereditary pulmonary alveolar proteinosis.

What condition is associated with SFTPC p.Thr65= (c.195G>A)?

SFTPC p.Thr65= (c.195G>A) is associated with hereditary pulmonary alveolar proteinosis (ClinVar).

How common is SFTPC p.Thr65= (c.195G>A) in the general population?

SFTPC p.Thr65= (c.195G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

How is Hereditary pulmonary alveolar proteinosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SFTPC p.Thr65=

c.195G>A · rs188074517 · VCV1783398

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

hereditary pulmonary alveolar proteinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP -15	GERP -2.5
Overall
CADD	0.464	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,030 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00254% 41/1,614,154 alleles · ultra-rare exomes 38/1,461,828 · genomes 3/152,326 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,576
South Asian	0.00549%	18,218
European (non-Finnish)	0.00237%	42,143
East Asian	0.00223%	44,882

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.Thr65=
Coding: c.195G>A
MANE Select: NM_001317778
dbSNP: rs188074517
Type: single nucleotide variant
Location: chr8:22162726 (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

hereditary pulmonary alveolar proteinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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.Ile73Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
SFTPC p.Leu110Pro Pathogenic/Likely pathogenic ★★ same condition
SFTPC p.Ile50Met Uncertain significance ★★ ⚠ same condition
SFTPC c.43-7G>A Benign/Likely benign ★★ same condition
SFTPC c.435+12T>G Benign/Likely benign ★★ same condition
SFTPC c.435+15G>A Benign/Likely benign ★★ same condition
SFTPC c.*12T>A Benign/Likely benign ★★ same condition
SFTPC p.Arg23Gln Benign/Likely benign ★★ 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-thr65 (accessed [today's date]).

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