Is TFRC p.Phe660Ser (c.1979T>C) pathogenic?

TFRC p.Phe660Ser (c.1979T>C) is classified Uncertain significance in TFRC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-02). AlphaMissense: likely benign (0.3351); Absent from gnomAD v4.1.

How common is TFRC p.Phe660Ser (c.1979T>C) in the general population?

TFRC p.Phe660Ser (c.1979T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TFRC p.Phe660Ser (c.1979T>C)?

AlphaMissense predicts likely benign (score 0.3351) — an in-silico prediction, not a clinical call.

TFRC p.Phe660Ser

c.1979T>C · VCV3685045

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3351 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3351	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -8.14	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 3.7	GERP 0.65, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0021 · regional, not allelic
Overall
CADD	23.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TFRC
Protein: p.Phe660Ser
Coding: c.1979T>C
MANE Select: NM_001128148
Type: single nucleotide variant
Location: chr3:196053479 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 24 PDB
Residue 660: an α-helix; the 'ligand-binding' region

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

Similar variants

TFRC p.Phe660= Likely benign ★ 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-phe660ser (accessed [today's date]).

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