Is CHFR p.Leu552Pro (c.1655T>C) pathogenic?

CHFR p.Leu552Pro (c.1655T>C) is classified Uncertain significance in CHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: likely pathogenic (0.9946); Ultra-rare (popmax 0.0317%, amr).

How common is CHFR p.Leu552Pro (c.1655T>C) in the general population?

CHFR p.Leu552Pro (c.1655T>C) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

What do computational predictors say about CHFR p.Leu552Pro (c.1655T>C)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

CHFR p.Leu552Pro

c.1655T>C · rs1008556440 · VCV2399207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic · top 4% in CHFR
REVEL	0.799	moderately pathogenic-leaning
SaProt	LLR -16.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 12 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	31.0	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 L564P vs ClinVar L552P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0317% Admixed American · 19/59,996 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00186% 30/1,613,570 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,158
Remaining individualsnot grpmax-eligible	0.0112%	8,921
African / African-American	0.00534%	18,730

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.Leu552Pro
Coding: c.1655T>C
MANE Select: NM_001161346
dbSNP: rs1008556440
Type: single nucleotide variant
Location: chr12:132847123 (GRCh38)
Gene constraint: LOEUF 0.929 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.22 · 6 PDB
Residue 552: a turn

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-leu552pro (accessed [today's date]).

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