Is TNF p.Gly57Ser (c.169G>A) pathogenic?

TNF p.Gly57Ser (c.169G>A) is classified Uncertain significance in TNF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). AlphaMissense: likely benign (0.1827); Very rare (popmax 0.00189%, amr).

How common is TNF p.Gly57Ser (c.169G>A) in the general population?

TNF p.Gly57Ser (c.169G>A) is very rare (popmax 0.00189%, amr) (gnomAD).

What do computational predictors say about TNF p.Gly57Ser (c.169G>A)?

AlphaMissense predicts likely benign (score 0.1827) — an in-silico prediction, not a clinical call.

TNF p.Gly57Ser

c.169G>A · VCV4597303

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1827 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00189%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1827	likely benign
REVEL	0.565	indeterminate
SaProt	LLR -4.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	29.3	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 0.00189% Admixed American · 1/52,858 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.00032% 5/1,562,908 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00189%	52,858
European (non-Finnish)	0.000347%	288,569

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.Gly57Ser
Coding: c.169G>A
MANE Select: NM_000594
Type: single nucleotide variant
Location: chr6:31575910 (GRCh38)
Gene constraint: LOEUF 0.592 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 84.72 · 52 PDB

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.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-gly57ser (accessed [today's date]).

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