Is CLMN p.Asp592Glu (c.1776C>G) pathogenic?

CLMN p.Asp592Glu (c.1776C>G) is classified Uncertain significance in CLMN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). AlphaMissense: likely benign (0.0891); Ultra-rare (popmax 0.02%, amr).

How common is CLMN p.Asp592Glu (c.1776C>G) in the general population?

CLMN p.Asp592Glu (c.1776C>G) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about CLMN p.Asp592Glu (c.1776C>G)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

CLMN p.Asp592Glu

c.1776C>G · rs144975674 · VCV2387922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -4.71	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 -10	GERP -4.9
Regional constraint	o/e 0.94	unconstrained · MANE · 128 kb · p 0.024 · regional, not allelic
Overall
CADD	0.002	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 0.02% Admixed American · 12/60,018 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00124% 20/1,614,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.0112%	8,929
African / African-American	0.00133%	75,008

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: CLMN
Protein: p.Asp592Glu
Coding: c.1776C>G
MANE Select: NM_024734
dbSNP: rs144975674
Type: single nucleotide variant
Location: chr14:95203573 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.84
Residue 592: the 'disordered' region

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

Similar variants

CLMN p.Asp592= Benign ★★ same residue
CLMN c.2511+10C>T Benign ★★ same type
CLMN c.886-4G>T Likely benign ★★ same type
CLMN p.Glu276Lys Likely benign ★★ same type
CLMN p.Glu357Lys Benign ★★ same type
CLMN p.Glu771Ala Likely benign ★★ same type
CLMN p.His518= Benign ★★ same type
CLMN p.Ile900Phe Benign ★★ 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/clmn-p-asp592glu (accessed [today's date]).

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