Is SETD5 p.His505Pro (c.1514A>C) pathogenic?

SETD5 p.His505Pro (c.1514A>C) is classified Uncertain significance in SETD5 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0641); Ultra-rare (popmax 0.0845%, nfe); Associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency.

How common is SETD5 p.His505Pro (c.1514A>C) in the general population?

SETD5 p.His505Pro (c.1514A>C) is ultra-rare (popmax 0.0845%, nfe) (gnomAD).

What do computational predictors say about SETD5 p.His505Pro (c.1514A>C)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

SETD5 p.His505Pro

Q: What condition is associated with SETD5 p.His505Pro (c.1514A>C)?

SETD5 p.His505Pro (c.1514A>C) is associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

c.1514A>C · rs2125243380 · VCV3234942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0845%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -4.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.9	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · regional, not allelic
Overall
CADD	22.6	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 0.0845% European (non-Finnish) · 992/1,173,378 alleles

Filtering AF 0.0802% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0784%

Overall 0.0678% 1,089/1,605,694 alleles · ultra-rare exomes 1,088/1,453,408 · genomes 1/152,286 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0845%	1,183
Remaining individualsnot grpmax-eligible	0.0563%	1,776
African / African-American	0.0334%	2,993
South Asian	0.0254%	3,942
Ashkenazi Jewishnot grpmax-eligible	0.0204%	4,912
East Asian	0.0112%	8,953
Admixed American	0.00335%	29,861
Finnishnot grpmax-eligible	0.00157%	63,788

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.His505Pro
Coding: c.1514A>C
MANE Select: NM_001080517
dbSNP: rs2125243380
Type: single nucleotide variant
Location: chr3:9445730 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 505: the 'disordered' region; a UniProt-annotated variant site (in mrd23)

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

Disease context

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD5 p.His505Tyr Uncertain significance ★★ ⚠ same residue
SETD5 p.His505= Benign ★★ same residue
SETD5 c.1441-1G>A Pathogenic ★★ same condition
SETD5 c.1525-1G>C Pathogenic/Likely pathogenic ★★ same condition
SETD5 c.2347-7A>G Pathogenic ★★ same condition
SETD5 c.3631+1G>A Pathogenic ★★ same condition
SETD5 c.960-5C>G Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Arg1001Ter Pathogenic ★★ 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/setd5-p-his505pro (accessed [today's date]).

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