Is CHRD p.Pro751Leu (c.2252C>T) pathogenic?

CHRD p.Pro751Leu (c.2252C>T) is classified Uncertain significance in CHRD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-25). AlphaMissense: likely benign (0.093); Ultra-rare (popmax 0.0165%, mid).

How common is CHRD p.Pro751Leu (c.2252C>T) in the general population?

CHRD p.Pro751Leu (c.2252C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CHRD p.Pro751Leu (c.2252C>T)?

AlphaMissense predicts likely benign (score 0.093) — an in-silico prediction, not a clinical call.

CHRD p.Pro751Leu

c.2252C>T · rs146476400 · VCV3144551

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.093	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -13.12	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,100 bp · p 0.0047 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00198% 32/1,614,224 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.00668%	14,960
South Asian	0.00329%	30,363
African / African-American	0.00266%	37,539
European (non-Finnish)	0.00186%	53,638
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Pro751Leu
Coding: c.2252C>T
MANE Select: NM_003741
dbSNP: rs146476400
Type: single nucleotide variant
Location: chr3:184386900 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.95 · 3 PDB
Residue 751: the vwfc 2 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-pro751leu (accessed [today's date]).

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