Is GEMIN5 p.Ser604Phe (c.1811C>T) pathogenic?

GEMIN5 p.Ser604Phe (c.1811C>T) is classified Uncertain significance in GEMIN5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-30). AlphaMissense: likely pathogenic (0.992); Ultra-rare (popmax 0.0414%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GEMIN5 p.Ser604Phe (c.1811C>T)?

GEMIN5 p.Ser604Phe (c.1811C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GEMIN5 p.Ser604Phe (c.1811C>T) in the general population?

GEMIN5 p.Ser604Phe (c.1811C>T) is ultra-rare (popmax 0.0414%, nfe) (gnomAD).

What do computational predictors say about GEMIN5 p.Ser604Phe (c.1811C>T)?

AlphaMissense predicts likely pathogenic (score 0.992) — an in-silico prediction, not a clinical call.

GEMIN5 p.Ser604Phe

c.1811C>T · rs142769106 · VCV1700925

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.992 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0414%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.992	likely pathogenic · top 3% in GEMIN5
REVEL	0.483	indeterminate
SaProt	LLR -15.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 50 kb · p 0.51 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0414% European (non-Finnish) · 486/1,173,450 alleles

Filtering AF 0.0384% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0371%

Overall 0.0315% 505/1,605,026 alleles · ultra-rare exomes 477/1,452,764 · genomes 28/152,262 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0414%	2,415
Remaining individualsnot grpmax-eligible	0.0113%	8,863
African / African-American	0.00801%	12,481
Finnishnot grpmax-eligible	0.00783%	12,767
Admixed American	0.00168%	59,630

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: GEMIN5
Protein: p.Ser604Phe
Coding: c.1811C>T
MANE Select: NM_015465
dbSNP: rs142769106
Type: single nucleotide variant
Location: chr5:154917042 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.17 · 16 PDB
Residue 604: a β-strand; a UniProt-annotated variant site (in nedcam)

Full GEMIN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GEMIN5 p.Arg1284His Uncertain significance ★★ ⚠ same condition
GEMIN5 p.Leu1127Pro Uncertain significance ★★ ⚠ same condition
GEMIN5 p.Leu1359His Uncertain significance ★★ ⚠ same condition
GEMIN5 p.Lys742Arg Uncertain significance ★★ ⚠ same condition
GEMIN5 p.Ser394Phe Uncertain significance ★★ ⚠ same condition
GEMIN5 p.Ser543Gly Uncertain significance ★★ ⚠ same condition
GEMIN5 p.Thr1439Ile Uncertain significance ★★ ⚠ same condition
GEMIN5 p.Val1157Met Uncertain significance ★★ ⚠ same condition

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/gemin5-p-ser604phe (accessed [today's date]).

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