Is TSFM p.Arg8Pro (c.23G>C) pathogenic?

TSFM p.Arg8Pro (c.23G>C) is classified Uncertain significance in TSFM (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-07). AlphaMissense: likely benign (0.104); Absent from gnomAD v4.1.

How common is TSFM p.Arg8Pro (c.23G>C) in the general population?

TSFM p.Arg8Pro (c.23G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSFM p.Arg8Pro (c.23G>C)?

AlphaMissense predicts likely benign (score 0.104) — an in-silico prediction, not a clinical call.

TSFM p.Arg8Pro

c.23G>C · rs763668656 · VCV1359716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.104 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.104	likely benign
REVEL	0.399	indeterminate
SaProt	LLR -6.31	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 3.1	GERP 0.41, phastCons 0.35
Regional constraint	o/e 1.15	unconstrained · MANE · 4,331 bp · p 0.04 · regional, not allelic
Overall
CADD	16.98	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSFM
Protein: p.Arg8Pro
Coding: c.23G>C
MANE Select: NM_005726
dbSNP: rs763668656
Type: single nucleotide variant
Location: chr12:57782824 (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

Similar variants

TSFM p.Arg8Cys Uncertain significance ★★ ⚠ same residue
TSFM p.Arg8= Conflicting classifications of pathogenicity ★ same residue
TSFM c.231+1G>A Likely pathogenic ★★ same type
TSFM c.232-2A>G Likely pathogenic ★★ same type
TSFM c.484-1G>A Likely pathogenic ★★ same type
TSFM c.484-1G>T Likely pathogenic ★★ same type
TSFM c.57+1G>A Likely pathogenic ★★ same type
TSFM c.571+1G>C Pathogenic/Likely pathogenic ★★ 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/tsfm-p-arg8pro (accessed [today's date]).

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