Is GEMIN4 p.Phe782Leu (c.2346C>G) pathogenic?

GEMIN4 p.Phe782Leu (c.2346C>G) is classified Benign in GEMIN4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely pathogenic (0.9562); Low-frequency (popmax 1.74%, afr).

How common is GEMIN4 p.Phe782Leu (c.2346C>G) in the general population?

GEMIN4 p.Phe782Leu (c.2346C>G) is low-frequency (popmax 1.74%, afr) (gnomAD).

What do computational predictors say about GEMIN4 p.Phe782Leu (c.2346C>G)?

AlphaMissense predicts likely pathogenic (score 0.9562) — an in-silico prediction, not a clinical call.

GEMIN4 p.Phe782Leu

c.2346C>G · rs34452716 · VCV787987

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9562 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.74%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9562	likely pathogenic · top 3% in GEMIN4
REVEL	0.193	benign-leaning
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,807 bp · p 0.23 · regional, not allelic
Overall
CADD	18.02	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.74% African / African-American · 1,297/74,692 alleles

Filtering AF 1.66% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.63%

Overall 0.0898% 1,436/1,599,256 alleles · low-frequency exomes 690/1,446,928 · genomes 746/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.74%	58
Remaining individualsnot grpmax-eligible	0.116%	862
Admixed American	0.0926%	1,080
Middle Eastern	0.0165%	6,048
South Asian	0.00672%	14,878
European (non-Finnish)	0.000597%	167,624

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: GEMIN4
Protein: p.Phe782Leu
Coding: c.2346C>G
MANE Select: NM_015721
dbSNP: rs34452716
Type: single nucleotide variant
Location: chr17:745697 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.54
Residue 782: a UniProt-annotated variant site (in)

Full GEMIN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GEMIN4 p.Trp818Arg Pathogenic/Likely pathogenic ★★ same type
GEMIN4 p.Ala186Val Uncertain significance ★★ ⚠ same type
GEMIN4 p.Arg91Gln Uncertain significance ★★ ⚠ same type
GEMIN4 p.Gln1032Ter Uncertain significance ★★ same type
GEMIN4 p.Gly814Glu Uncertain significance ★★ ⚠ same type
GEMIN4 p.Ile406Val Uncertain significance ★★ ⚠ same type
GEMIN4 p.Leu178Val Uncertain significance ★★ ⚠ same type
GEMIN4 p.Ser755Phe 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/gemin4-p-phe782leu (accessed [today's date]).

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