Is SFTPC p.Ala178Val (c.533C>T) pathogenic?

SFTPC p.Ala178Val (c.533C>T) is classified Uncertain significance in SFTPC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely benign (0.164); Very rare (popmax 0.000254%, nfe).

How common is SFTPC p.Ala178Val (c.533C>T) in the general population?

SFTPC p.Ala178Val (c.533C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about SFTPC p.Ala178Val (c.533C>T)?

AlphaMissense predicts likely benign (score 0.164) — an in-silico prediction, not a clinical call.

SFTPC p.Ala178Val

c.533C>T · VCV4087945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.164	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.4, phastCons 0.41
Regional constraint	o/e 0.87	unconstrained · MANE · 2,209 bp · p 0.036 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A184V vs ClinVar A178V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,026 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,534 alleles · very rare exomes 3/1,460,152 · genomes 0/152,382 · joint denominator

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.Ala178Val
Coding: c.533C>T
MANE Select: NM_001317778
Type: single nucleotide variant
Location: chr8:22163998 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.71 · 3 PDB
Residue 184 UniProt numbering: the brichos domain; an α-helix

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

Similar variants

SFTPC c.435+2T>C Pathogenic/Likely pathogenic ★★ same type
SFTPC p.Ile73Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
SFTPC p.Leu110Pro Pathogenic/Likely pathogenic ★★ same type
SFTPC p.Leu55Phe Likely pathogenic ★★ ⚠ same type
SFTPC c.*193C>A Uncertain significance ★★ same type
SFTPC p.Gly4Ser Uncertain significance ★★ ⚠ same type
SFTPC p.Ile50Met Uncertain significance ★★ ⚠ same type
SFTPC p.Leu45Pro Uncertain significance ★★ ⚠ same type

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-ala178val (accessed [today's date]).

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