Is TF p.Pro589Ser (c.1765C>T) pathogenic?

TF p.Pro589Ser (c.1765C>T) is classified Benign in TF (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0906); Common (popmax 24.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with atransferrinemia.

What condition is associated with TF p.Pro589Ser (c.1765C>T)?

TF p.Pro589Ser (c.1765C>T) is associated with atransferrinemia (ClinVar).

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.Pro589Ser (c.1765C>T)?

AlphaMissense predicts likely benign (score 0.0906) — an in-silico prediction, not a clinical call.

TF p.Pro589Ser

Q: How common is TF p.Pro589Ser (c.1765C>T) in the general population?

TF p.Pro589Ser (c.1765C>T) is common (popmax 24.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1765C>T · rs1049296 · VCV12617

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0906 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 24.6%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atransferrinemia

Computational evidence

Protein change
AlphaMissense	0.0906	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -8.96	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 -20	GERP -4.1
Regional constraint	o/e 0.85	unconstrained · MANE · 32 kb · p 8.3e-06 · regional, not allelic
Overall
CADD	0.001	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 24.6% East Asian · 11,039/44,864 alleles

Filtering AF 24.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.1%

Overall 16.2% 261,806/1,613,992 alleles · common exomes 240,815/1,461,786 · genomes 20,991/152,206 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	24.6%	4
Middle Eastern	21.7%	5
South Asian	21.3%	5
Ashkenazi Jewishnot grpmax-eligible	21.1%	5
Amishnot grpmax-eligible	17.7%	6
Remaining individualsnot grpmax-eligible	17%	6
European (non-Finnish)	16.3%	6
Admixed American	12.9%	8
Finnishnot grpmax-eligible	10.9%	9
African / African-American	7.78%	13

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.Pro589Ser
Coding: c.1765C>T
MANE Select: NM_001063
dbSNP: rs1049296
Type: single nucleotide variant
Location: chr3:133775510 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.39 · 69 PDB
Residue 589: a β-strand; the transferrin-like 2 domain; a UniProt-annotated variant site (in allele tf*c2)

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-pro589ser (accessed [today's date]).

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