Is TFRC p.Pro399Arg (c.1196C>G) pathogenic?

TFRC p.Pro399Arg (c.1196C>G) is classified Uncertain significance in TFRC (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-04). AlphaMissense: likely benign (0.1923); Very rare (popmax 0.000297%, nfe).

How common is TFRC p.Pro399Arg (c.1196C>G) in the general population?

TFRC p.Pro399Arg (c.1196C>G) is very rare (popmax 0.000297%, nfe) (gnomAD).

What do computational predictors say about TFRC p.Pro399Arg (c.1196C>G)?

AlphaMissense predicts likely benign (score 0.1923) — an in-silico prediction, not a clinical call.

TFRC p.Pro399Arg

c.1196C>G · rs1317596998 · VCV1525106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000297%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1923	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -9.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0021 · regional, not allelic
Overall
CADD	29.3	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 0.000297% European (non-Finnish) · 2/673,936 alleles

Filtering AF 4.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00024% 2/833,762 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.Pro399Arg
Coding: c.1196C>G
MANE Select: NM_001128148
dbSNP: rs1317596998
Type: single nucleotide variant
Location: chr3:196065445 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 24 PDB
Residue 399: a β-strand

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

Similar variants

TFRC p.Pro399Ser 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-pro399arg (accessed [today's date]).

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