Is CLUH p.Pro917Leu (c.2750C>T) pathogenic?

CLUH p.Pro917Leu (c.2750C>T) is classified Uncertain significance in CLUH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-07). AlphaMissense: likely benign (0.0536); Ultra-rare (popmax 0.0402%, amr).

How common is CLUH p.Pro917Leu (c.2750C>T) in the general population?

CLUH p.Pro917Leu (c.2750C>T) is ultra-rare (popmax 0.0402%, amr) (gnomAD).

What do computational predictors say about CLUH p.Pro917Leu (c.2750C>T)?

AlphaMissense predicts likely benign (score 0.0536) — an in-silico prediction, not a clinical call.

CLUH p.Pro917Leu

c.2750C>T · rs750782828 · VCV3146151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0536 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0402%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0536	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -7.86	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 2.1	GERP -0.38, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 10 kb · p 0.061 · regional, not allelic
Overall
CADD	13.47	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P878L vs ClinVar P917L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0402% Admixed American · 24/59,764 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0235%

Overall 0.00397% 64/1,612,150 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0402%	2,490
South Asian	0.0066%	15,142
European (non-Finnish)	0.00271%	36,850
Remaining individualsnot grpmax-eligible	0.0016%	62,356
African / African-American	0.00134%	74,900

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: CLUH
Protein: p.Pro917Leu
Coding: c.2750C>T
MANE Select: NM_001366661
dbSNP: rs750782828
Type: single nucleotide variant
Location: chr17:2694959 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.11

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

Similar variants

CLUH p.Ala671Val Benign ★★ same type
CLUH p.Ala700= Likely benign ★★ same type
CLUH p.Glu1228= Likely benign ★★ same type
CLUH p.Thr201= Benign ★★ same type
CLUH c.1025+1G>A Uncertain significance ★ same type
CLUH p.Ala1076Thr Uncertain significance ★ ⚠ same type
CLUH p.Ala1257Ser Uncertain significance ★ ⚠ same type
CLUH p.Ala1320Gly 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/cluh-p-pro917leu (accessed [today's date]).

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