Is TF p.Ala365= (c.1095G>A) pathogenic?

TF p.Ala365= (c.1095G>A) is classified Conflicting classifications of pathogenicity in TF (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.066%, mid); Associated with atransferrinemia.

What condition is associated with TF p.Ala365= (c.1095G>A)?

TF p.Ala365= (c.1095G>A) is associated with atransferrinemia (ClinVar).

How common is TF p.Ala365= (c.1095G>A) in the general population?

TF p.Ala365= (c.1095G>A) is ultra-rare (popmax 0.066%, mid) (gnomAD).

How is Congenital atransferrinemia inherited?

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

TF p.Ala365=

c.1095G>A · rs575999145 · VCV730768

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

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 -6.1	GERP -3.5
Overall
CADD	2.364	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.0139% 224/1,614,036 alleles · ultra-rare exomes 199/1,461,834 · genomes 25/152,202 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.193%	519
Middle Easterngrpmax	0.066%	1,516
Admixed American	0.0433%	2,309
Remaining individualsnot grpmax-eligible	0.0256%	3,906
South Asian	0.0165%	6,071
Finnishnot grpmax-eligible	0.00937%	10,667
European (non-Finnish)	0.00839%	11,919
African / African-American	0.00133%	75,012

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: TF
Protein: p.Ala365=
Coding: c.1095G>A
MANE Select: NM_001063
dbSNP: rs575999145
Type: single nucleotide variant
Location: chr3:133759221 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.39 · 69 PDB
Residue 365: a β-strand; the transferrin-like 2 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-ala365 (accessed [today's date]).

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