Is TSFM p.Ser215Phe (c.644C>T) pathogenic?

TSFM p.Ser215Phe (c.644C>T) is classified Conflicting classifications of pathogenicity in TSFM (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-04-23). AlphaMissense: likely benign (0.2342); Ultra-rare (popmax 0.0385%, sas); Associated with Inborn genetic diseases.

How common is TSFM p.Ser215Phe (c.644C>T) in the general population?

TSFM p.Ser215Phe (c.644C>T) is ultra-rare (popmax 0.0385%, sas) (gnomAD).

What do computational predictors say about TSFM p.Ser215Phe (c.644C>T)?

AlphaMissense predicts likely benign (score 0.2342) — an in-silico prediction, not a clinical call.

TSFM p.Ser215Phe

Q: What condition is associated with TSFM p.Ser215Phe (c.644C>T)?

TSFM p.Ser215Phe (c.644C>T) is associated with Inborn genetic diseases, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, nephrotic syndrome, type 21 (ClinVar).

c.644C>T · rs376562033 · VCV418526

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2342 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2342	likely benign
REVEL	0.738	pathogenic-leaning
SaProt	LLR -13.66	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,578 bp · p 0.37 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0385% South Asian · 35/90,982 alleles

Filtering AF 0.0284% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.0157% 254/1,613,290 alleles · ultra-rare exomes 238/1,461,092 · genomes 16/152,198 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0385%	2,599
East Asian	0.0267%	3,741
Middle Eastern	0.0164%	6,084
European (non-Finnish)	0.0163%	6,144
Remaining individualsnot grpmax-eligible	0.016%	6,244
Admixed American	0.005%	19,981
African / African-American	0.00133%	74,910

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.Ser215Phe
Coding: c.644C>T
MANE Select: NM_005726
dbSNP: rs376562033
Type: single nucleotide variant
Location: chr12:57796249 (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

Also linked: fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 nephrotic syndrome, type 21

Similar variants

TSFM p.Ser215Cys Uncertain significance ★★ ⚠ same residue
TSFM c.231+1G>A Likely pathogenic ★★ same condition
TSFM c.232-2A>G Likely pathogenic ★★ same condition
TSFM c.484-1G>A Likely pathogenic ★★ same condition
TSFM c.484-1G>T Likely pathogenic ★★ same condition
TSFM c.57+1G>A Likely pathogenic ★★ same condition
TSFM c.571+1G>C Pathogenic/Likely pathogenic ★★ same condition
TSFM p.Arg201Ter Pathogenic/Likely pathogenic ★★ 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-ser215phe (accessed [today's date]).

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