Is CHFR p.Arg555Ile (c.1664G>T) pathogenic?

CHFR p.Arg555Ile (c.1664G>T) is classified Uncertain significance in CHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: likely pathogenic (0.5803); Very rare (popmax 0.00133%, afr).

How common is CHFR p.Arg555Ile (c.1664G>T) in the general population?

CHFR p.Arg555Ile (c.1664G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CHFR p.Arg555Ile (c.1664G>T)?

AlphaMissense predicts likely pathogenic (score 0.5803) — an in-silico prediction, not a clinical call.

CHFR p.Arg555Ile

c.1664G>T · VCV3832968

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5803	likely pathogenic
REVEL	0.422	indeterminate
SaProt	LLR -10.81	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 12 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	29.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R567I vs ClinVar R555I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,016 alleles

Overall 0.000657% 1/152,234 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: CHFR
Protein: p.Arg555Ile
Coding: c.1664G>T
MANE Select: NM_001161346
Type: single nucleotide variant
Location: chr12:132847114 (GRCh38)
Gene constraint: LOEUF 0.929 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.22 · 6 PDB
Residue 555: an α-helix

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

Similar variants

CHFR p.Leu472= Benign ★★ same type
CHFR p.Gln411Ter Likely pathogenic ★ same type
CHFR p.Ala279Val Uncertain significance ★ ⚠ same type
CHFR p.Ala280Ser Uncertain significance ★ ⚠ same type
CHFR p.Ala499Val Uncertain significance ★ ⚠ same type
CHFR p.Ala569Val Uncertain significance ★ ⚠ same type
CHFR p.Arg21His Uncertain significance ★ ⚠ same type
CHFR p.Arg266Gly 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/chfr-p-arg555ile (accessed [today's date]).

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