Is CLUH p.Ser905Phe (c.2714C>T) pathogenic?

CLUH p.Ser905Phe (c.2714C>T) is classified Uncertain significance in CLUH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-17). AlphaMissense: ambiguous (0.3937); Very rare (popmax 0.005%, amr).

How common is CLUH p.Ser905Phe (c.2714C>T) in the general population?

CLUH p.Ser905Phe (c.2714C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CLUH p.Ser905Phe (c.2714C>T)?

AlphaMissense predicts ambiguous (score 0.3937) — an in-silico prediction, not a clinical call.

CLUH p.Ser905Phe

c.2714C>T · VCV3494037

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3937	ambiguous
REVEL	0.672	pathogenic-leaning
SaProt	LLR -10.17	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense 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	28.1	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 S866F vs ClinVar S905F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,952 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000372% 6/1,613,546 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,984
African / African-American	0.00267%	37,465
Remaining individualsnot grpmax-eligible	0.0016%	62,438

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.Ser905Phe
Coding: c.2714C>T
MANE Select: NM_001366661
Type: single nucleotide variant
Location: chr17:2694995 (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-ser905phe (accessed [today's date]).

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