Is CLUH p.Ser208Arg (c.624C>A) pathogenic?

CLUH p.Ser208Arg (c.624C>A) is classified Uncertain significance in CLUH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-06). AlphaMissense: ambiguous (0.5405); Ultra-rare (popmax 0.0164%, amr).

How common is CLUH p.Ser208Arg (c.624C>A) in the general population?

CLUH p.Ser208Arg (c.624C>A) is ultra-rare (popmax 0.0164%, amr) (gnomAD).

What do computational predictors say about CLUH p.Ser208Arg (c.624C>A)?

AlphaMissense predicts ambiguous (score 0.5405) — an in-silico prediction, not a clinical call.

CLUH p.Ser208Arg

c.624C>A · rs75023474 · VCV3146160

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5405 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, amr)

Computational evidence

Protein change
AlphaMissense	0.5405	ambiguous
REVEL	0.498	indeterminate
SaProt	LLR -6.61	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	GERP -4.3, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 2,691 bp · p 6.9e-06 · regional, not allelic
Overall
CADD	18.0	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 S170R vs ClinVar S208R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Admixed American · 9/54,914 alleles

Filtering AF 0.00848% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00635%

Overall 0.00275% 43/1,562,520 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0164%	6,102
Remaining individualsnot grpmax-eligible	0.00666%	15,008
European (non-Finnish)	0.0026%	38,473

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.Ser208Arg
Coding: c.624C>A
MANE Select: NM_001366661
dbSNP: rs75023474
Type: single nucleotide variant
Location: chr17:2701733 (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-ser208arg (accessed [today's date]).

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