Is SETD5 p.Met993Val (c.2977A>G) pathogenic?

SETD5 p.Met993Val (c.2977A>G) is classified Conflicting classifications of pathogenicity in SETD5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-10-19). AlphaMissense: likely benign (0.1184); Ultra-rare (popmax 0.0549%, sas); Associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency.

How common is SETD5 p.Met993Val (c.2977A>G) in the general population?

SETD5 p.Met993Val (c.2977A>G) is ultra-rare (popmax 0.0549%, sas) (gnomAD).

What do computational predictors say about SETD5 p.Met993Val (c.2977A>G)?

AlphaMissense predicts likely benign (score 0.1184) — an in-silico prediction, not a clinical call.

SETD5 p.Met993Val

Q: What condition is associated with SETD5 p.Met993Val (c.2977A>G)?

SETD5 p.Met993Val (c.2977A>G) is associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

c.2977A>G · rs779084293 · VCV2200969

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1184 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0549%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.1184	likely benign
REVEL	0.675	pathogenic-leaning
SaProt	LLR -4.80	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · regional, not allelic
Overall
CADD	24.1	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 0.0549% South Asian · 50/91,088 alleles

Filtering AF 0.0427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.00967% 156/1,613,908 alleles · ultra-rare exomes 148/1,461,708 · genomes 8/152,200 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0549%	1,822
Remaining individualsnot grpmax-eligible	0.00961%	10,411
European (non-Finnish)	0.00848%	11,799

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.Met993Val
Coding: c.2977A>G
MANE Select: NM_001080517
dbSNP: rs779084293
Type: single nucleotide variant
Location: chr3:9470711 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 993: 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.Met993Leu Uncertain significance ★ ⚠ 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
SETD5 p.Arg1072Ter Pathogenic/Likely 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-met993val (accessed [today's date]).

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