Is TF p.Arg42His (c.125G>A) pathogenic?

TF p.Arg42His (c.125G>A) is classified Uncertain significance in TF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-13). AlphaMissense: likely benign (0.1209); Ultra-rare (popmax 0.022%, sas).

How common is TF p.Arg42His (c.125G>A) in the general population?

TF p.Arg42His (c.125G>A) is ultra-rare (popmax 0.022%, sas) (gnomAD).

What do computational predictors say about TF p.Arg42His (c.125G>A)?

AlphaMissense predicts likely benign (score 0.1209) — an in-silico prediction, not a clinical call.

TF p.Arg42His

c.125G>A · rs41298293 · VCV1900205

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1209 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1209	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -7.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.6	GERP -0.47
Regional constraint	o/e 0.85	unconstrained · MANE · 32 kb · p 8.3e-06 · regional, not allelic
Overall
CADD	15.38	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 0.022% South Asian · 20/91,084 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00341% 55/1,614,110 alleles · ultra-rare exomes 51/1,461,890 · genomes 4/152,220 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.022%	4,554
European (non-Finnish)	0.0028%	35,759
East Asian	0.00223%	44,842
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: TF
Protein: p.Arg42His
Coding: c.125G>A
MANE Select: NM_001063
dbSNP: rs41298293
Type: single nucleotide variant
Location: chr3:133748493 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.39 · 69 PDB
Residue 42: the transferrin-like 1 domain; a modified residue (dimethylated arginine); a UniProt-annotated variant site (in); an α-helix

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

Similar variants

TF p.Arg42= Likely benign ★ same residue
TF p.Arg42Leu Benign ★ same residue
TF c.-18C>T Uncertain significance ★★ same type
TF p.Ala318Ser Uncertain significance ★★ ⚠ same type
TF p.Ala72Val Uncertain significance ★★ ⚠ same type
TF p.Gln264Glu Uncertain significance ★★ ⚠ same type
TF p.Gln559Leu Uncertain significance ★★ ⚠ same type
TF p.Ile229Thr 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/tf-p-arg42his (accessed [today's date]).

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