Is GEMIN4 p.Phe433= (c.1299C>T) pathogenic?

GEMIN4 p.Phe433= (c.1299C>T) is classified Benign in GEMIN4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.77%, mid).

How common is GEMIN4 p.Phe433= (c.1299C>T) in the general population?

GEMIN4 p.Phe433= (c.1299C>T) is low-frequency (popmax 1.77%, mid) (gnomAD).

GEMIN4 p.Phe433=

c.1299C>T · rs147516197 · VCV778650

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.77%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Overall
CADD	8.434	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.77% Middle Eastern · 107/6,062 alleles

Filtering AF 1.49% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.39%

Overall 0.802% 12,949/1,613,752 alleles · low-frequency exomes 11,970/1,461,456 · genomes 979/152,296 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.97%	34
Middle Easterngrpmax	1.77%	57
East Asian	1.29%	77
South Asian	1.06%	94
Remaining individualsnot grpmax-eligible	0.834%	120
European (non-Finnish)	0.802%	125
Admixed American	0.465%	215
African / African-American	0.119%	843
Finnishnot grpmax-eligible	0.103%	967

Ashkenazi Jewish 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: GEMIN4
Protein: p.Phe433=
Coding: c.1299C>T
MANE Select: NM_015721
dbSNP: rs147516197
Type: single nucleotide variant
Location: chr17:746744 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.54

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-phe433 (accessed [today's date]).

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