Is CHRD p.Pro486Leu (c.1457C>T) pathogenic?

CHRD p.Pro486Leu (c.1457C>T) is classified Uncertain significance in CHRD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely benign (0.0778); Very rare (popmax 0.00594%, nfe).

How common is CHRD p.Pro486Leu (c.1457C>T) in the general population?

CHRD p.Pro486Leu (c.1457C>T) is very rare (popmax 0.00594%, nfe) (gnomAD).

What do computational predictors say about CHRD p.Pro486Leu (c.1457C>T)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

CHRD p.Pro486Leu

c.1457C>T · rs146324922 · VCV3144542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00594%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -0.47, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,100 bp · p 0.0047 · regional, not allelic
Overall
CADD	19.23	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 0.00594% European (non-Finnish) · 69/1,162,306 alleles

Filtering AF 0.00477% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00437%

Overall 0.00457% 72/1,576,878 alleles · very rare exomes 70/1,424,686 · genomes 2/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00594%	16,845
Remaining individualsnot grpmax-eligible	0.00164%	60,814
Finnishnot grpmax-eligible	0.00162%	61,610
African / African-American	0.00135%	74,000

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.Pro486Leu
Coding: c.1457C>T
MANE Select: NM_003741
dbSNP: rs146324922
Type: single nucleotide variant
Location: chr3:184384553 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.95 · 3 PDB
Residue 486: the chrd 3 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-pro486leu (accessed [today's date]).

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