Is TF p.His268= (c.804T>C) pathogenic?

TF p.His268= (c.804T>C) is classified Benign in TF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). Common (popmax 18.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with atransferrinemia.

What condition is associated with TF p.His268= (c.804T>C)?

TF p.His268= (c.804T>C) is associated with atransferrinemia (ClinVar).

How is Congenital atransferrinemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TF p.His268=

Q: How common is TF p.His268= (c.804T>C) in the general population?

TF p.His268= (c.804T>C) is common (popmax 18.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.804T>C · rs8177232 · VCV343440

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 18.9%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

atransferrinemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -11	GERP -4.3
Overall
CADD	0.208	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 18.9% African / African-American · 14,198/75,002 alleles

Filtering AF 18.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.6%

Overall 1.01% 16,367/1,614,086 alleles · common exomes 8,164/1,461,838 · genomes 8,203/152,248 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	18.9%	5
Admixed American	1.38%	73
Remaining individualsnot grpmax-eligible	1.32%	76
Middle Eastern	0.924%	108
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,691
European (non-Finnish)	0.0358%	2,790
South Asian	0.0329%	3,036

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.His268=
Coding: c.804T>C
MANE Select: NM_001063
dbSNP: rs8177232
Type: single nucleotide variant
Location: chr3:133756943 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.39 · 69 PDB
Residue 268: a binding site; the transferrin-like 1 domain

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

Disease context

atransferrinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital atransferrinemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

TF c.-18C>T Uncertain significance ★★ same condition
TF p.Ala72Val Uncertain significance ★★ ⚠ same condition
TF p.Gln264Glu Uncertain significance ★★ ⚠ same condition
TF p.Ile229Thr Uncertain significance ★★ ⚠ same condition
TF p.Thr112Ala Uncertain significance ★★ ⚠ same condition
TF p.Val451Ala Uncertain significance ★★ ⚠ same condition
TF c.1688-4C>A Benign/Likely benign ★★ same condition
TF c.216+14G>C Benign/Likely benign ★★ same condition

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-his268 (accessed [today's date]).

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