Is TF p.His319Arg (c.956A>G) pathogenic?

TF p.His319Arg (c.956A>G) is classified Benign in TF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0668); Low-frequency (popmax 1.35%, eas); Associated with atransferrinemia.

What condition is associated with TF p.His319Arg (c.956A>G)?

TF p.His319Arg (c.956A>G) is associated with atransferrinemia (ClinVar).

How common is TF p.His319Arg (c.956A>G) in the general population?

TF p.His319Arg (c.956A>G) is low-frequency (popmax 1.35%, eas) (gnomAD).

How is Congenital atransferrinemia inherited?

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

What do computational predictors say about TF p.His319Arg (c.956A>G)?

AlphaMissense predicts likely benign (score 0.0668) — an in-silico prediction, not a clinical call.

TF p.His319Arg

c.956A>G · rs41295774 · VCV12615

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0668 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.35%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atransferrinemia

Computational evidence

Protein change
AlphaMissense	0.0668	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.13	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 1.5	GERP -3.1
Regional constraint	o/e 0.85	unconstrained · MANE · 32 kb · p 8.3e-06 · regional, not allelic
Overall
CADD	4.832	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 1.35% East Asian · 604/44,886 alleles

Filtering AF 1.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.22%

Overall 0.122% 1,974/1,614,206 alleles · low-frequency exomes 1,599/1,461,886 · genomes 375/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.35%	74
Finnishnot grpmax-eligible	0.979%	102
Admixed American	0.563%	178
Remaining individualsnot grpmax-eligible	0.187%	534
South Asian	0.0878%	1,138
European (non-Finnish)	0.0173%	5,784
African / African-American	0.00533%	18,763

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.His319Arg
Coding: c.956A>G
MANE Select: NM_001063
dbSNP: rs41295774
Type: single nucleotide variant
Location: chr3:133757854 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.39 · 69 PDB
Residue 319: a β-strand; the transferrin-like 1 domain; a UniProt-annotated variant site (in allele tf*chi)

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 p.His319= Likely benign ★ same residue
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

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-his319arg (accessed [today's date]).

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