Is TFRC p.Arg155Pro (c.464G>C) pathogenic?

TFRC p.Arg155Pro (c.464G>C) is classified Uncertain significance in TFRC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-29). AlphaMissense: likely pathogenic (0.8234); Very rare (popmax 0.000508%, nfe); Associated with TFRC-related combined immunodeficiency.

What condition is associated with TFRC p.Arg155Pro (c.464G>C)?

TFRC p.Arg155Pro (c.464G>C) is associated with TFRC-related combined immunodeficiency (ClinVar).

How common is TFRC p.Arg155Pro (c.464G>C) in the general population?

TFRC p.Arg155Pro (c.464G>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about TFRC p.Arg155Pro (c.464G>C)?

AlphaMissense predicts likely pathogenic (score 0.8234) — an in-silico prediction, not a clinical call.

TFRC p.Arg155Pro

Q: How is Combined immunodeficiency due to TFRC deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.464G>C · rs775554571 · VCV1028098

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

TFRC-related combined immunodeficiency

Computational evidence

Protein change
AlphaMissense	0.8234	likely pathogenic
REVEL	0.472	indeterminate
SaProt	LLR -15.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0021 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000508% European (non-Finnish) · 6/1,179,948 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,650 alleles · very rare

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.Arg155Pro
Coding: c.464G>C
MANE Select: NM_001128148
dbSNP: rs775554571
Type: single nucleotide variant
Location: chr3:196072123 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 24 PDB
Residue 155: a β-strand

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

Disease context

TFRC-related combined immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to TFRC deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

TFRC p.Arg155His Uncertain significance ★★ ⚠ same residue
TFRC p.Arg155Cys Uncertain significance ★ same residue
TFRC c.1678-3C>T Uncertain significance ★★ same condition
TFRC p.Asn379Ser Uncertain significance ★★ ⚠ same condition
TFRC p.Asp245Gly Uncertain significance ★★ ⚠ same condition
TFRC c.1404+17C>A Benign/Likely benign ★★ same condition
TFRC c.1468+25G>T Benign ★★ same condition
TFRC c.1468+39A>G 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/tfrc-p-arg155pro (accessed [today's date]).

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