Is TNF p.Ile159= (c.477C>T) pathogenic?

TNF p.Ile159= (c.477C>T) is classified Likely benign in TNF (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-28). Rare (popmax 0.141%, afr).

How common is TNF p.Ile159= (c.477C>T) in the general population?

TNF p.Ile159= (c.477C>T) is rare (popmax 0.141%, afr) (gnomAD).

TNF p.Ile159=

c.477C>T · rs757398208 · VCV723481

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.141%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3
Overall
CADD	0.294	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.141% African / African-American · 106/74,940 alleles

Filtering AF 0.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.111%

Overall 0.0102% 164/1,613,126 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.141%	707
Remaining individualsnot grpmax-eligible	0.0096%	10,413
Admixed American	0.005%	20,003
South Asian	0.00439%	22,773
European (non-Finnish)	0.00381%	26,223

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: TNF
Protein: p.Ile159=
Coding: c.477C>T
MANE Select: NM_000594
dbSNP: rs757398208
Type: single nucleotide variant
Location: chr6:31577312 (GRCh38)
Gene constraint: LOEUF 0.592 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 84.72 · 52 PDB
Residue 159: a disulfide bond; a β-strand; the thd domain

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

Similar variants

TNF p.Pro84Leu Benign/Likely benign ★★ same type
TNF p.Arg107Leu Uncertain significance ★ ⚠ same type
TNF p.Asp66Asn Uncertain significance ★ ⚠ same type
TNF p.Gly184Arg Uncertain significance ★ ⚠ same type
TNF p.Gly54Glu Uncertain significance ★ ⚠ same type
TNF p.Gly57Ser Uncertain significance ★ ⚠ same type
TNF p.Met6Lys Uncertain significance ★ ⚠ same type
TNF p.Thr83Asn 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/tnf-p-ile159 (accessed [today's date]).

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