Is TFRC p.Ala166Val (c.497C>T) pathogenic?

TFRC p.Ala166Val (c.497C>T) is classified Uncertain significance in TFRC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-06). AlphaMissense: ambiguous (0.4873); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with TFRC p.Ala166Val (c.497C>T)?

TFRC p.Ala166Val (c.497C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TFRC p.Ala166Val (c.497C>T) in the general population?

TFRC p.Ala166Val (c.497C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about TFRC p.Ala166Val (c.497C>T)?

AlphaMissense predicts ambiguous (score 0.4873) — an in-silico prediction, not a clinical call.

TFRC p.Ala166Val

c.497C>T · rs771569167 · VCV1917250

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4873	ambiguous
REVEL	0.23	benign-leaning
SaProt	LLR -10.82	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -0.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0021 · regional, not allelic
Overall
CADD	21.7	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 0.00329% South Asian · 3/91,078 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000479% 7/1,461,814 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,359
African / African-American	0.00133%	75,016
European (non-Finnish)	0.000254%	393,331

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: TFRC
Protein: p.Ala166Val
Coding: c.497C>T
MANE Select: NM_001128148
dbSNP: rs771569167
Type: single nucleotide variant
Location: chr3:196072090 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 24 PDB
Residue 166: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TFRC p.Ala166= Likely benign ★ same residue
TFRC p.Ala196Thr Uncertain significance ★★ ⚠ same condition
TFRC p.Ala293Thr Uncertain significance ★★ ⚠ same condition
TFRC p.Ala540Val Uncertain significance ★★ ⚠ same condition
TFRC p.Ala72Ser Uncertain significance ★★ ⚠ same condition
TFRC p.Arg155His Uncertain significance ★★ ⚠ same condition
TFRC p.Arg613Ser Uncertain significance ★★ ⚠ same condition
TFRC p.Arg719Cys Uncertain significance ★★ ⚠ 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/tfrc-p-ala166val (accessed [today's date]).

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