Is TF p.Val48Ile (c.142G>A) pathogenic?

TF p.Val48Ile (c.142G>A) is classified Uncertain significance in TF (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.0806); Ultra-rare (popmax 0.033%, mid); Associated with atransferrinemia.

What condition is associated with TF p.Val48Ile (c.142G>A)?

TF p.Val48Ile (c.142G>A) is associated with atransferrinemia (ClinVar).

How common is TF p.Val48Ile (c.142G>A) in the general population?

TF p.Val48Ile (c.142G>A) is ultra-rare (popmax 0.033%, mid) (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.Val48Ile (c.142G>A)?

AlphaMissense predicts likely benign (score 0.0806) — an in-silico prediction, not a clinical call.

TF p.Val48Ile

c.142G>A · rs144636315 · VCV343425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0806 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atransferrinemia

Computational evidence

Protein change
AlphaMissense	0.0806	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.45	GERP -3.8
Regional constraint	o/e 0.85	unconstrained · MANE · 32 kb · p 8.3e-06 · regional, not allelic
Overall
CADD	2.954	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00242% 39/1,614,108 alleles · ultra-rare exomes 25/1,461,892 · genomes 14/152,216 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
African / African-American	0.024%	4,168
Finnishnot grpmax-eligible	0.00937%	10,670
South Asian	0.00549%	18,215
European (non-Finnish)	0.000678%	147,504

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.Val48Ile
Coding: c.142G>A
MANE Select: NM_001063
dbSNP: rs144636315
Type: single nucleotide variant
Location: chr3:133748510 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.39 · 69 PDB
Residue 48: the transferrin-like 1 domain; an α-helix

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-val48ile (accessed [today's date]).

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