Is MED16 p.Ile726Val (c.2176A>G) pathogenic?

MED16 p.Ile726Val (c.2176A>G) is classified Uncertain significance in MED16 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-14). AlphaMissense: likely benign (0.0931); Very rare (popmax 0.00119%, sas).

How common is MED16 p.Ile726Val (c.2176A>G) in the general population?

MED16 p.Ile726Val (c.2176A>G) is very rare (popmax 0.00119%, sas) (gnomAD).

What do computational predictors say about MED16 p.Ile726Val (c.2176A>G)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

MED16 p.Ile726Val

c.2176A>G · rs2512196755 · VCV2612183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -4.84	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 1	GERP -1.3, phastCons 0.99
Regional constraint	o/e 1.27	unconstrained · MANE · 23 kb · p 7.4e-22 · regional, not allelic
Overall
CADD	11.49	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 0.00119% South Asian · 1/84,112 alleles

Overall 7.16e-05% 1/1,397,168 alleles · very rare

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: MED16
Protein: p.Ile726Val
Coding: c.2176A>G
MANE Select: NM_005481
dbSNP: rs2512196755
Type: single nucleotide variant
Location: chr19:871176 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.25 · 10 PDB
Residue 726: a UniProt-annotated variant site (in ggns; likely pathogenic)

Full MED16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MED16 p.Arg456His Uncertain significance ★★ ⚠ same type
MED16 p.Arg701Cys Uncertain significance ★★ ⚠ same type
MED16 p.Asn826= Benign ★★ same type
MED16 p.Leu187= Benign ★★ same type
MED16 p.Thr189= Benign ★★ same type
MED16 p.Val590= Benign ★★ same type
MED16 c.880-2A>G Likely pathogenic ★ same type
MED16 c.1560+6G>T 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/med16-p-ile726val (accessed [today's date]).

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