Is TSFM p.Pro38Ser (c.112C>T) pathogenic?

TSFM p.Pro38Ser (c.112C>T) is classified Uncertain significance in TSFM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-07). AlphaMissense: likely benign (0.0723); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with TSFM p.Pro38Ser (c.112C>T)?

TSFM p.Pro38Ser (c.112C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TSFM p.Pro38Ser (c.112C>T) in the general population?

TSFM p.Pro38Ser (c.112C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TSFM p.Pro38Ser (c.112C>T)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

TSFM p.Pro38Ser

c.112C>T · rs368889346 · VCV2187316

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -5.79	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 -0.59	GERP -5.1
Regional constraint	o/e 1.15	unconstrained · MANE · 4,331 bp · p 0.04 · regional, not allelic
Overall
CADD	2.374	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000558% 9/1,613,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
South Asian	0.00549%	18,217
European (non-Finnish)	0.000254%	393,298

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: TSFM
Protein: p.Pro38Ser
Coding: c.112C>T
MANE Select: NM_005726
dbSNP: rs368889346
Type: single nucleotide variant
Location: chr12:57783164 (GRCh38)
Gene constraint: LOEUF 1.197 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.87 · 1 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TSFM p.Pro38Leu Uncertain significance ★★ ⚠ same residue
TSFM p.Pro38= Likely benign ★★ same residue
TSFM p.Pro38Thr Uncertain significance ★ ⚠ same residue
TSFM p.Ala174Val Uncertain significance ★★ ⚠ same condition
TSFM p.Ala20Val Uncertain significance ★★ ⚠ same condition
TSFM p.Ala220Thr Uncertain significance ★★ ⚠ same condition
TSFM p.Ala264Asp Uncertain significance ★★ ⚠ same condition
TSFM p.Arg255Cys 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/tsfm-p-pro38ser (accessed [today's date]).

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