Is SART3 p.Leu725Val (c.2173C>G) pathogenic?

SART3 p.Leu725Val (c.2173C>G) is classified Uncertain significance in SART3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely benign (0.0682); Very rare (popmax 0.00356%, nfe).

How common is SART3 p.Leu725Val (c.2173C>G) in the general population?

SART3 p.Leu725Val (c.2173C>G) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about SART3 p.Leu725Val (c.2173C>G)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

SART3 p.Leu725Val

c.2173C>G · VCV4159662

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 26 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	16.84	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 0.00356% European (non-Finnish) · 42/1,180,048 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00279% 45/1,614,116 alleles · very rare exomes 40/1,461,892 · genomes 5/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,096
Remaining individualsnot grpmax-eligible	0.0032%	31,245
African / African-American	0.00133%	74,932

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: SART3
Protein: p.Leu725Val
Coding: c.2173C>G
MANE Select: NM_014706
Type: single nucleotide variant
Location: chr12:108526296 (GRCh38)
Gene constraint: LOEUF 0.419 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.57 · 9 PDB
Residue 725: the rrm 1 domain; the 'necessary and sufficient for u6 snrna binding' region; an α-helix

Full SART3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SART3 c.1310-5G>A Benign/Likely benign ★★ same type
SART3 c.544+10C>T Benign/Likely benign ★★ same type
SART3 p.Arg370= Benign ★★ same type
SART3 p.Asn932= Benign ★★ same type
SART3 p.Asp691= Benign ★★ same type
SART3 p.Ala237Gly Uncertain significance ★ ⚠ same type
SART3 p.Ala237Val Uncertain significance ★ ⚠ same type
SART3 p.Ala241Ser 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/sart3-p-leu725val (accessed [today's date]).

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