Is TRAF2 p.Phe56Ser (c.167T>C) pathogenic?

TRAF2 p.Phe56Ser (c.167T>C) is classified Uncertain significance in TRAF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.1082); Very rare (popmax 0.00267%, afr).

How common is TRAF2 p.Phe56Ser (c.167T>C) in the general population?

TRAF2 p.Phe56Ser (c.167T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TRAF2 p.Phe56Ser (c.167T>C)?

AlphaMissense predicts likely benign (score 0.1082) — an in-silico prediction, not a clinical call.

TRAF2 p.Phe56Ser

c.167T>C · VCV4598486

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1082	likely benign
REVEL	0.399	indeterminate
SaProt	LLR -2.03	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 -1.5	GERP -2.3
Overall
CADD	7.548	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 0.00267% African / African-American · 2/74,814 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00137% 22/1,610,154 alleles · very rare exomes 20/1,458,022 · genomes 2/152,132 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,530
African / African-Americangrpmax	0.00267%	37,407
South Asian	0.00221%	45,313
Admixed American	0.00168%	59,688
European (non-Finnish)	0.00136%	73,681

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TRAF2
Protein: p.Phe56Ser
Coding: c.167T>C
MANE Select: NM_021138
Type: single nucleotide variant
Location: chr9:136898907 (GRCh38)
Structure: AlphaFold pLDDT 60.31 · 3 PDB

Full TRAF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TANK p.Gln113Glu Benign ★★ same type
TRAF2 p.Arg308= Benign ★★ same type
TRAF2 p.Gly81= Benign ★★ same type
TRAF2 p.Phe361= Benign ★★ same type
TANK p.Arg40Ser Uncertain significance ★ ⚠ same type
TANK p.Arg42Cys Uncertain significance ★ ⚠ same type
TANK p.Asn87Ser Uncertain significance ★ ⚠ same type
TANK p.Asn88Ile 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/traf2-p-phe56ser (accessed [today's date]).

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