Is TF p.Gly538= (c.1614C>T) pathogenic?

TF p.Gly538= (c.1614C>T) is classified Benign in TF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-31). Low-frequency (popmax 3.91%, afr); Associated with atransferrinemia.

What condition is associated with TF p.Gly538= (c.1614C>T)?

TF p.Gly538= (c.1614C>T) is associated with atransferrinemia (ClinVar).

How common is TF p.Gly538= (c.1614C>T) in the general population?

TF p.Gly538= (c.1614C>T) is low-frequency (popmax 3.91%, afr) (gnomAD).

How is Congenital atransferrinemia inherited?

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

TF p.Gly538=

c.1614C>T · rs8177286 · VCV343446

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.91%, afr)

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 1.3	GERP -3.8, phastCons 1
Overall
CADD	10.86	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.91% African / African-American · 2,932/75,020 alleles

Filtering AF 3.79% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.74%

Overall 0.211% 3,406/1,614,156 alleles · low-frequency exomes 1,740/1,461,876 · genomes 1,666/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.91%	26
Remaining individualsnot grpmax-eligible	0.274%	366
Admixed American	0.255%	392
Middle Eastern	0.198%	505
East Asian	0.0223%	4,488
South Asian	0.0165%	6,072
European (non-Finnish)	0.00958%	10,443

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.Gly538=
Coding: c.1614C>T
MANE Select: NM_001063
dbSNP: rs8177286
Type: single nucleotide variant
Location: chr3:133768156 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.39 · 69 PDB
Residue 538: an α-helix; 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-gly538 (accessed [today's date]).

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