Is CHMP4A p.Leu7Phe (c.19C>T) pathogenic?

CHMP4A p.Leu7Phe (c.19C>T) is classified Uncertain significance in CHMP4A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-25). AlphaMissense: likely benign (0.1139); Very rare (popmax 0.00976%, nfe).

How common is CHMP4A p.Leu7Phe (c.19C>T) in the general population?

CHMP4A p.Leu7Phe (c.19C>T) is very rare (popmax 0.00976%, nfe) (gnomAD).

What do computational predictors say about CHMP4A p.Leu7Phe (c.19C>T)?

AlphaMissense predicts likely benign (score 0.1139) — an in-silico prediction, not a clinical call.

CHMP4A p.Leu7Phe

c.19C>T · VCV3492377

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1139 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00976%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1139	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -7.69	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 3	GERP 0.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,559 bp · p 0.17 · regional, not allelic
Overall
CADD	22.2	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 0.00976% European (non-Finnish) · 115/1,178,234 alleles

Filtering AF 0.00827% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00775%

Overall 0.00778% 125/1,607,384 alleles · very rare exomes 116/1,455,226 · genomes 9/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00976%	10,246
Admixed American	0.00676%	14,797
African / African-American	0.00535%	18,677
Remaining individualsnot grpmax-eligible	0.00321%	31,131

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: CHMP4A
Protein: p.Leu7Phe
Coding: c.19C>T
MANE Select: NM_014169
Type: single nucleotide variant
Location: chr14:24213421 (GRCh38)
Gene constraint: LOEUF 1.343 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 2 PDB
Residue 7: the 'intramolecular interaction with c-terminus' region; the 'interaction with phosphoinosides' region; the 'disordered' region

Full CHMP4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHMP4A c.-21G>A Uncertain significance ★ same type
CHMP4A c.-35C>T Uncertain significance ★ same type
CHMP4A c.-48G>A Uncertain significance ★ same type
CHMP4A p.Ala77Val Uncertain significance ★ ⚠ same type
CHMP4A p.Arg104His Uncertain significance ★ ⚠ same type
CHMP4A p.Arg148Gln Uncertain significance ★ ⚠ same type
CHMP4A p.Arg148Trp Uncertain significance ★ ⚠ same type
CHMP4A p.Arg67Gln 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/chmp4a-p-leu7phe (accessed [today's date]).

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