Is TFRC p.Pro354= (c.1062C>T) pathogenic?

TFRC p.Pro354= (c.1062C>T) is classified Likely benign in TFRC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). Ultra-rare (popmax 0.0455%, sas).

How common is TFRC p.Pro354= (c.1062C>T) in the general population?

TFRC p.Pro354= (c.1062C>T) is ultra-rare (popmax 0.0455%, sas) (gnomAD).

TFRC p.Pro354=

c.1062C>T · rs753583737 · VCV2173440

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0455%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP -2.5, phastCons 0.001
Overall
CADD	2.026	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0455% South Asian · 41/90,072 alleles

Filtering AF 0.0344% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0306%

Overall 0.00292% 47/1,607,164 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0455%	2,197
Remaining individualsnot grpmax-eligible	0.00161%	62,236
European (non-Finnish)	0.000424%	235,699

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.Pro354=
Coding: c.1062C>T
MANE Select: NM_001128148
dbSNP: rs753583737
Type: single nucleotide variant
Location: chr3:196065579 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 24 PDB
Residue 354: a disulfide bond

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

Similar variants

TFRC p.Pro354Arg 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
TFRC p.Ala72Ser Uncertain significance ★★ ⚠ same type
TFRC p.Arg155His 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-pro354 (accessed [today's date]).

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