Is SIX5 p.Pro596Arg (c.1787C>G) pathogenic?

SIX5 p.Pro596Arg (c.1787C>G) is classified Uncertain significance in SIX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). AlphaMissense: likely benign (0.1503); Very rare (popmax 0.00103%, nfe).

How common is SIX5 p.Pro596Arg (c.1787C>G) in the general population?

SIX5 p.Pro596Arg (c.1787C>G) is very rare (popmax 0.00103%, nfe) (gnomAD).

What do computational predictors say about SIX5 p.Pro596Arg (c.1787C>G)?

AlphaMissense predicts likely benign (score 0.1503) — an in-silico prediction, not a clinical call.

SIX5 p.Pro596Arg

c.1787C>G · VCV3700603

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1503 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00103%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1503	likely benign
REVEL	0.298	indeterminate
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.29	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 2,547 bp · p 3e-11 · regional, not allelic
Overall
CADD	24.1	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 0.00103% European (non-Finnish) · 12/1,169,404 alleles

Filtering AF 0.000547% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000432%

Overall 0.000816% 13/1,593,234 alleles · very rare exomes 12/1,441,032 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00162%	61,652
European (non-Finnish)grpmax	0.00103%	97,451

Remaining individuals 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: SIX5
Protein: p.Pro596Arg
Coding: c.1787C>G
MANE Select: NM_175875
Type: single nucleotide variant
Location: chr19:45765934 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.21

Full SIX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SIX5 p.Pro596Leu Uncertain significance ★ ⚠ same residue
SIX5 p.Ala408Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala411Val Uncertain significance ★★ ⚠ same type
SIX5 p.Ala584Val Uncertain significance ★★ ⚠ same type
SIX5 p.Ala626Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala649Ser Uncertain significance ★★ ⚠ same type
SIX5 p.Ala673Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala722Gly 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/six5-p-pro596arg (accessed [today's date]).

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