Is SMC5 p.Pro73Ser (c.217C>T) pathogenic?

SMC5 p.Pro73Ser (c.217C>T) is classified Uncertain significance in SMC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: likely benign (0.2493); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with SMC5 p.Pro73Ser (c.217C>T)?

SMC5 p.Pro73Ser (c.217C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SMC5 p.Pro73Ser (c.217C>T) in the general population?

SMC5 p.Pro73Ser (c.217C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SMC5 p.Pro73Ser (c.217C>T)?

AlphaMissense predicts likely benign (score 0.2493) — an in-silico prediction, not a clinical call.

SMC5 p.Pro73Ser

c.217C>T · rs759486297 · VCV2619006

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2493 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2493	likely benign
REVEL	0.543	indeterminate
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 22 kb · p 0.75 · regional, not allelic
Overall
CADD	26.9	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 0.00223% East Asian · 1/44,858 alleles

Overall 0.000137% 2/1,461,612 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,858
European (non-Finnish)	8.48e-05%	1,179,866

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: SMC5
Protein: p.Pro73Ser
Coding: c.217C>T
MANE Select: NM_015110
dbSNP: rs759486297
Type: single nucleotide variant
Location: chr9:70264335 (GRCh38)
Gene constraint: LOEUF 0.716 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 4 PDB

Full SMC5 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

SMC5 p.Glu226Lys Uncertain significance ★★ same condition
SMC5 p.Ala166Ser Uncertain significance ★ ⚠ same condition
SMC5 p.Ala615Val Uncertain significance ★ ⚠ same condition
SMC5 p.Ala735Thr Uncertain significance ★ ⚠ same condition
SMC5 p.Ala791Thr Uncertain significance ★ ⚠ same condition
SMC5 p.Ala870Thr Uncertain significance ★ ⚠ same condition
SMC5 p.Arg1031Trp Uncertain significance ★ ⚠ same condition
SMC5 p.Arg1091Gln 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/smc5-p-pro73ser (accessed [today's date]).

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