Is TF p.Ala76Val (c.227C>T) pathogenic?

TF p.Ala76Val (c.227C>T) is classified Likely benign in TF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.2318); Rare (popmax 0.428%, eas); Associated with atransferrinemia.

What condition is associated with TF p.Ala76Val (c.227C>T)?

TF p.Ala76Val (c.227C>T) is associated with atransferrinemia (ClinVar).

How common is TF p.Ala76Val (c.227C>T) in the general population?

TF p.Ala76Val (c.227C>T) is rare (popmax 0.428%, 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.Ala76Val (c.227C>T)?

AlphaMissense predicts likely benign (score 0.2318) — an in-silico prediction, not a clinical call.

TF p.Ala76Val

c.227C>T · rs41298977 · VCV902173

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2318 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.428%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

atransferrinemia

Computational evidence

Protein change
AlphaMissense	0.2318	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -10.82	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 32 kb · p 8.3e-06 · regional, not allelic
Overall
CADD	24.3	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 0.428% East Asian · 192/44,878 alleles

Filtering AF 0.378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.359%

Overall 0.0168% 271/1,614,062 alleles · rare exomes 241/1,461,818 · genomes 30/152,244 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.428%	234
South Asian	0.0362%	2,760
Remaining individualsnot grpmax-eligible	0.0256%	3,907
African / African-American	0.00267%	37,516
European (non-Finnish)	0.00229%	43,702
Admixed American	0.00167%	60,022

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.Ala76Val
Coding: c.227C>T
MANE Select: NM_001063
dbSNP: rs41298977
Type: single nucleotide variant
Location: chr3:133753605 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.39 · 69 PDB
Residue 76: the transferrin-like 1 domain; a UniProt-annotated variant site (in)

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.Ala76= 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-ala76val (accessed [today's date]).

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