Is CHM p.Ser558Thr (c.1672T>A) pathogenic?

CHM p.Ser558Thr (c.1672T>A) is classified Uncertain significance in CHM (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-02-05). AlphaMissense: likely benign (0.0932); Very rare (popmax 0.000337%, nfe); Associated with choroideremia.

What condition is associated with CHM p.Ser558Thr (c.1672T>A)?

CHM p.Ser558Thr (c.1672T>A) is associated with choroideremia (ClinVar).

How common is CHM p.Ser558Thr (c.1672T>A) in the general population?

CHM p.Ser558Thr (c.1672T>A) is very rare (popmax 0.000337%, nfe) (gnomAD).

How is Choroideremia inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHM p.Ser558Thr (c.1672T>A)?

AlphaMissense predicts likely benign (score 0.0932) — an in-silico prediction, not a clinical call.

CHM p.Ser558Thr

c.1672T>A · VCV4064687

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000337%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

choroideremia

Computational evidence

Protein change
AlphaMissense	0.0932	likely benign
REVEL	0.492	indeterminate
SaProt	LLR -1.34	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 183 kb · p 0.28 · regional, not allelic
Overall
CADD	17.59	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000337% European (non-Finnish) · 3/891,360 alleles

Filtering AF 9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000332% 4/1,204,919 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00211%	47,383
European (non-Finnish)grpmax	0.000337%	297,120

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CHM
Protein: p.Ser558Thr
Coding: c.1672T>A
MANE Select: NM_000390
Type: single nucleotide variant
Location: chrX:85873150 (GRCh38)
Structure: AlphaFold pLDDT 81.05

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

Disease context

choroideremia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Choroideremia (Orphanet):

Inheritance: X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CHM p.Ser558Ter Pathogenic ★ same residue
CHM c.116+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHM c.116+1G>T Pathogenic/Likely pathogenic ★★ same condition
CHM c.1166+1G>A Pathogenic ★★ same condition
CHM c.1166+1G>C Pathogenic ★★ same condition
CHM c.1350-1G>A Pathogenic/Likely pathogenic ★★ same condition
CHM c.1413+1G>T Pathogenic ★★ same condition
CHM c.1511-1G>A Pathogenic ★★ same condition

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/chm-p-ser558thr (accessed [today's date]).

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