Is TFRC p.Ala487Val (c.1460C>T) pathogenic?

TFRC p.Ala487Val (c.1460C>T) is classified Uncertain significance in TFRC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-02). AlphaMissense: likely benign (0.1165); Very rare (popmax 0.00668%, eas).

How common is TFRC p.Ala487Val (c.1460C>T) in the general population?

TFRC p.Ala487Val (c.1460C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about TFRC p.Ala487Val (c.1460C>T)?

AlphaMissense predicts likely benign (score 0.1165) — an in-silico prediction, not a clinical call.

TFRC p.Ala487Val

c.1460C>T · rs563023109 · VCV2980785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1165 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1165	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -6.78	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 5	GERP -0.22, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0021 · regional, not allelic
Overall
CADD	18.98	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 0.00668% East Asian · 3/44,878 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00137% 22/1,607,582 alleles · very rare exomes 18/1,455,292 · genomes 4/152,290 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0141%	7,107
East Asiangrpmax	0.00668%	14,959
African / African-American	0.00268%	37,314
Admixed American	0.00173%	57,832
Remaining individualsnot grpmax-eligible	0.00161%	62,292
European (non-Finnish)	0.000509%	196,358

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala487Val
Coding: c.1460C>T
MANE Select: NM_001128148
dbSNP: rs563023109
Type: single nucleotide variant
Location: chr3:196062590 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 24 PDB

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

Similar variants

TFRC p.Ala487= Likely benign ★★ same residue
TFRC p.Ala487Ser Uncertain significance ★ ⚠ same residue
TFRC p.Ala487Thr Uncertain significance ★ ⚠ same residue
TFRC c.1678-3C>T Uncertain significance ★★ same type
TFRC p.Ala166Val Uncertain significance ★★ ⚠ same type
TFRC p.Ala196Thr Uncertain significance ★★ ⚠ same type
TFRC p.Ala293Thr Uncertain significance ★★ ⚠ same type
TFRC p.Ala540Val 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/tfrc-p-ala487val (accessed [today's date]).

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