Is TF p.Ala405Val (c.1214C>T) pathogenic?

TF p.Ala405Val (c.1214C>T) is classified Uncertain significance in TF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-13). AlphaMissense: ambiguous (0.3708); Very rare (popmax 0.00119%, nfe).

How common is TF p.Ala405Val (c.1214C>T) in the general population?

TF p.Ala405Val (c.1214C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about TF p.Ala405Val (c.1214C>T)?

AlphaMissense predicts ambiguous (score 0.3708) — an in-silico prediction, not a clinical call.

TF p.Ala405Val

c.1214C>T · rs149754236 · VCV2352321

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3708 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3708	ambiguous
REVEL	0.596	indeterminate
SaProt	LLR -8.22	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 32 kb · p 8.3e-06 · regional, not allelic
Overall
CADD	29.5	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 0.00119% European (non-Finnish) · 14/1,179,788 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000868% 14/1,613,716 alleles · very rare exomes 12/1,461,530 · genomes 2/152,186 · joint denominator

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.Ala405Val
Coding: c.1214C>T
MANE Select: NM_001063
dbSNP: rs149754236
Type: single nucleotide variant
Location: chr3:133764192 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.39 · 69 PDB
Residue 405: the transferrin-like 2 domain

Full TF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TF c.-18C>T Uncertain significance ★★ same type
TF p.Ala318Ser Uncertain significance ★★ ⚠ same type
TF p.Ala72Val Uncertain significance ★★ ⚠ same type
TF p.Gln264Glu Uncertain significance ★★ ⚠ same type
TF p.Gln559Leu Uncertain significance ★★ ⚠ same type
TF p.Ile229Thr Uncertain significance ★★ ⚠ same type
TF p.Thr112Ala Uncertain significance ★★ ⚠ same type
TF p.Val270Asp Uncertain significance ★★ ⚠ same type

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-ala405val (accessed [today's date]).

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