Is TNF p.Pro84Leu (c.251C>T) pathogenic?

TNF p.Pro84Leu (c.251C>T) is classified Benign/Likely benign in TNF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.082); Low-frequency (popmax 1.81%, mid).

How common is TNF p.Pro84Leu (c.251C>T) in the general population?

TNF p.Pro84Leu (c.251C>T) is low-frequency (popmax 1.81%, mid) (gnomAD).

What do computational predictors say about TNF p.Pro84Leu (c.251C>T)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

TNF p.Pro84Leu

c.251C>T · rs4645843 · VCV781865

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.81%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.188	benign-leaning
SaProt	LLR -6.72	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 0.67	GERP -2.4
Overall
CADD	16.35	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 1.81% Middle Eastern · 110/6,062 alleles

Filtering AF 1.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.44%

Overall 0.181% 2,927/1,612,964 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.81%	55
Ashkenazi Jewishnot grpmax-eligible	1.07%	94
South Asian	0.441%	227
Remaining individualsnot grpmax-eligible	0.282%	355
Admixed American	0.277%	361
European (non-Finnish)	0.144%	695
African / African-American	0.06%	1,667
Finnishnot grpmax-eligible	0.0175%	5,722
East Asian	0.00446%	22,440

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.Pro84Leu
Coding: c.251C>T
MANE Select: NM_000594
dbSNP: rs4645843
Type: single nucleotide variant
Location: chr6:31576785 (GRCh38)
Gene constraint: LOEUF 0.592 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 84.72 · 52 PDB
Residue 84: a UniProt-annotated variant site (in); an α-helix

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

Similar variants

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
TNF p.Val117Ala 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-pro84leu (accessed [today's date]).

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