Is CLUH p.Ala900Asp (c.2699C>A) pathogenic?

CLUH p.Ala900Asp (c.2699C>A) is classified Uncertain significance in CLUH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely pathogenic (0.6218); Ultra-rare (popmax 0.0197%, nfe).

How common is CLUH p.Ala900Asp (c.2699C>A) in the general population?

CLUH p.Ala900Asp (c.2699C>A) is ultra-rare (popmax 0.0197%, nfe) (gnomAD).

What do computational predictors say about CLUH p.Ala900Asp (c.2699C>A)?

AlphaMissense predicts likely pathogenic (score 0.6218) — an in-silico prediction, not a clinical call.

CLUH p.Ala900Asp

c.2699C>A · rs753855649 · VCV2467668

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6218 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6218	likely pathogenic
REVEL	0.364	indeterminate
SaProt	LLR -6.69	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 2.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 10 kb · p 0.061 · regional, not allelic
Overall
CADD	23.9	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 A861D vs ClinVar A900D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0197% European (non-Finnish) · 232/1,179,826 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0168%

Overall 0.0152% 245/1,613,540 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0197%	5,085
Remaining individualsnot grpmax-eligible	0.0112%	8,920
Admixed American	0.00834%	11,993
African / African-American	0.00133%	74,938

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.Ala900Asp
Coding: c.2699C>A
MANE Select: NM_001366661
dbSNP: rs753855649
Type: single nucleotide variant
Location: chr17:2695010 (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.Ala900Thr Uncertain significance ★ ⚠ same residue
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

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-ala900asp (accessed [today's date]).

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