Is SETD5 p.Arg64Pro (c.191G>C) pathogenic?

SETD5 p.Arg64Pro (c.191G>C) is classified Benign/Likely benign in SETD5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.7827); Ultra-rare (popmax 0.02%, amr).

How common is SETD5 p.Arg64Pro (c.191G>C) in the general population?

SETD5 p.Arg64Pro (c.191G>C) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about SETD5 p.Arg64Pro (c.191G>C)?

AlphaMissense predicts likely pathogenic (score 0.7827) — an in-silico prediction, not a clinical call.

SETD5 p.Arg64Pro

c.191G>C · rs368353953 · VCV736003

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7827	likely pathogenic
REVEL	0.362	indeterminate
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 12 kb · p 2.7e-05 · regional, not allelic
Overall
CADD	27.6	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 0.02% Admixed American · 12/59,980 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00954% 154/1,613,618 alleles · ultra-rare exomes 141/1,461,574 · genomes 13/152,044 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.365%	274
Remaining individualsnot grpmax-eligible	0.024%	4,164
Admixed Americangrpmax	0.02%	4,998
European (non-Finnish)	0.00161%	62,093

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: SETD5
Protein: p.Arg64Pro
Coding: c.191G>C
MANE Select: NM_001080517
dbSNP: rs368353953
Type: single nucleotide variant
Location: chr3:9434347 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10

Full SETD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD5 p.Arg64Cys Uncertain significance ★★ same residue
SETD5 p.Arg64Gly Uncertain significance ★★ ⚠ same residue
SETD5 p.Arg64His Likely benign ★★ same residue
SETD5 c.1441-1G>A Pathogenic ★★ same type
SETD5 c.1525-1G>C Pathogenic/Likely pathogenic ★★ same type
SETD5 c.2347-1G>A Pathogenic ★★ same type
SETD5 c.2347-7A>G Pathogenic ★★ same type
SETD5 c.3631+1G>A Pathogenic ★★ 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/setd5-p-arg64pro (accessed [today's date]).

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