Is CHMP7 p.Lys393Arg (c.1178A>G) pathogenic?

CHMP7 p.Lys393Arg (c.1178A>G) is classified Uncertain significance in CHMP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.0741); Very rare (popmax 0.004%, afr).

How common is CHMP7 p.Lys393Arg (c.1178A>G) in the general population?

CHMP7 p.Lys393Arg (c.1178A>G) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CHMP7 p.Lys393Arg (c.1178A>G)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

CHMP7 p.Lys393Arg

c.1178A>G · VCV4653462

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 0.99, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.075 · regional, not allelic
Overall
CADD	20.5	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 0.004% African / African-American · 3/74,924 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000496% 8/1,614,066 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
Admixed American	0.00167%	60,008
European (non-Finnish)	0.000339%	295,011

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: CHMP7
Protein: p.Lys393Arg
Coding: c.1178A>G
MANE Select: NM_152272
Type: single nucleotide variant
Location: chr8:23260201 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.53
Residue 393: the 'disordered' region

Full CHMP7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHMP7 p.Ala297= Benign ★★ same type
CHMP7 p.Leu347= Benign ★★ same type
CHMP7 p.Ala112Asp Uncertain significance ★ ⚠ same type
CHMP7 p.Ala12Gly Uncertain significance ★ ⚠ same type
CHMP7 p.Ala146Thr Uncertain significance ★ ⚠ same type
CHMP7 p.Ala160Gly Uncertain significance ★ ⚠ same type
CHMP7 p.Ala17Thr Uncertain significance ★ ⚠ same type
CHMP7 p.Ala188Val 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/chmp7-p-lys393arg (accessed [today's date]).

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