Is TF p.Leu486Val (c.1456C>G) pathogenic?

TF p.Leu486Val (c.1456C>G) is classified Uncertain significance in TF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely benign (0.2364); Very rare (popmax 0.00373%, nfe).

How common is TF p.Leu486Val (c.1456C>G) in the general population?

TF p.Leu486Val (c.1456C>G) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about TF p.Leu486Val (c.1456C>G)?

AlphaMissense predicts likely benign (score 0.2364) — an in-silico prediction, not a clinical call.

TF p.Leu486Val

c.1456C>G · rs771354238 · VCV2252979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2364 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2364	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -10.18	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.65	GERP -4.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 32 kb · p 8.3e-06 · regional, not allelic
Overall
CADD	22.0	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 0.00373% European (non-Finnish) · 44/1,180,036 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00291% 47/1,614,084 alleles · very rare exomes 42/1,461,860 · genomes 5/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,819
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00133%	74,922

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.Leu486Val
Coding: c.1456C>G
MANE Select: NM_001063
dbSNP: rs771354238
Type: single nucleotide variant
Location: chr3:133766403 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.39 · 69 PDB
Residue 486: the transferrin-like 2 domain

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

Similar variants

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
TF p.Thr112Ala Uncertain significance ★★ ⚠ same type
TF p.Val270Asp 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-leu486val (accessed [today's date]).

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