Is CLUH p.Pro230Ser (c.688C>T) pathogenic?

CLUH p.Pro230Ser (c.688C>T) is classified Uncertain significance in CLUH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely pathogenic (0.9813); Very rare (popmax 0.00134%, afr).

How common is CLUH p.Pro230Ser (c.688C>T) in the general population?

CLUH p.Pro230Ser (c.688C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CLUH p.Pro230Ser (c.688C>T)?

AlphaMissense predicts likely pathogenic (score 0.9813) — an in-silico prediction, not a clinical call.

CLUH p.Pro230Ser

c.688C>T · VCV4003963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9813 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9813	likely pathogenic
REVEL	0.494	indeterminate
SaProt	LLR -9.52	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 2,691 bp · p 6.9e-06 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P192S vs ClinVar P230S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,696 alleles

Overall 0.000657% 1/152,218 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: CLUH
Protein: p.Pro230Ser
Coding: c.688C>T
MANE Select: NM_001366661
Type: single nucleotide variant
Location: chr17:2701669 (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-pro230ser (accessed [today's date]).

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