Is CHRD p.Phe53Leu (c.159C>G) pathogenic?

CHRD p.Phe53Leu (c.159C>G) is classified Uncertain significance in CHRD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.9735); Very rare (popmax 0.00173%, amr).

How common is CHRD p.Phe53Leu (c.159C>G) in the general population?

CHRD p.Phe53Leu (c.159C>G) is very rare (popmax 0.00173%, amr) (gnomAD).

What do computational predictors say about CHRD p.Phe53Leu (c.159C>G)?

AlphaMissense predicts likely pathogenic (score 0.9735) — an in-silico prediction, not a clinical call.

CHRD p.Phe53Leu

c.159C>G · VCV4653529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00173%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9735	likely pathogenic · top 5% in CHRD
REVEL	0.393	indeterminate
SaProt	LLR -11.02	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 3.8	GERP 0.95, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,100 bp · p 0.0047 · regional, not allelic
Overall
CADD	25.7	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 0.00173% Admixed American · 1/57,924 alleles

Overall 6.97e-05% 1/1,435,742 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: CHRD
Protein: p.Phe53Leu
Coding: c.159C>G
MANE Select: NM_003741
Type: single nucleotide variant
Location: chr3:184380702 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.95 · 3 PDB
Residue 53: the vwfc 1 domain

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

Similar variants

CHRD p.Gln608= Benign ★★ same type
CHRD p.Gly387Ser Benign ★★ same type
CHRD p.Pro772= Benign ★★ same type
CHRD p.Thr301= Benign ★★ same type
CHRD p.Thr457Ser Likely benign ★★ same type
CHRD p.Ala251Glu Uncertain significance ★ ⚠ same type
CHRD p.Ala251Thr Uncertain significance ★ ⚠ same type
CHRD p.Ala27Pro 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/chrd-p-phe53leu (accessed [today's date]).

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