Is CHRD p.Pro2Leu (c.5C>T) pathogenic?

CHRD p.Pro2Leu (c.5C>T) is classified Uncertain significance in CHRD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2892); Very rare (popmax 0.00185%, nfe).

How common is CHRD p.Pro2Leu (c.5C>T) in the general population?

CHRD p.Pro2Leu (c.5C>T) is very rare (popmax 0.00185%, nfe) (gnomAD).

What do computational predictors say about CHRD p.Pro2Leu (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2892) — an in-silico prediction, not a clinical call.

CHRD p.Pro2Leu

c.5C>T · VCV4653526

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2892 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00185%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2892	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.57	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 4.3	GERP 0.72, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,100 bp · p 0.0047 · regional, not allelic
Overall
CADD	23.8	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 0.00185% European (non-Finnish) · 19/1,029,398 alleles

Filtering AF 0.00118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000951%

Overall 0.00165% 22/1,330,792 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00554%	18,038
European (non-Finnish)grpmax	0.00185%	54,179
South Asian	0.00153%	65,452

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro2Leu
Coding: c.5C>T
MANE Select: NM_003741
Type: single nucleotide variant
Location: chr3:184380323 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.95 · 3 PDB

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-pro2leu (accessed [today's date]).

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