Is SDHD p.Met91fs (c.270_271del) pathogenic?

SDHD p.Met91fs (c.270271del) is classified Likely pathogenic in SDHD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). Very rare (popmax 0.0011%, sas); Associated with Inherited phaeochromocytoma and paraganglioma excluding NF1.

What condition is associated with SDHD p.Met91fs (c.270_271del)?

SDHD p.Met91fs (c.270_271del) is associated with Inherited phaeochromocytoma and paraganglioma excluding NF1 (ClinVar).

How common is SDHD p.Met91fs (c.270_271del) in the general population?

SDHD p.Met91fs (c.270_271del) is very rare (popmax 0.0011%, sas) (gnomAD).

SDHD p.Met91fs

c.270_271del · VCV4281639

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Inherited phaeochromocytoma and paraganglioma excluding NF1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (3 of 4, 44 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.21	GERP -1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Overall 6.2e-05% 1/1,614,132 alleles · very rare exomes 1/1,461,830 · genomes 0/152,302 · joint denominator

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: SDHD
Protein: p.Met91fs
Coding: c.270_271del
MANE Select: NM_003002
Type: Deletion
Location: chr11:112088967 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 91: an α-helix

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

Disease context

Inherited phaeochromocytoma and paraganglioma excluding NF1

Similar variants

SDHD p.Met91Leu Uncertain significance ★★ ⚠ same residue
SDHD p.Met91Lys Uncertain significance ★★ ⚠ same residue
SDHD p.Met91Thr Uncertain significance ★★ ⚠ same residue
SDHD p.Ala133fs Likely pathogenic ★ same condition
SDHD p.Met91Ile Uncertain significance ★ ⚠ same residue
SDHD p.Met91Val Uncertain significance ★ ⚠ same residue
SDHD c.315-1681_315-1666del Likely pathogenic same condition
SDHD p.Arg70Met 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/sdhd-p-met91fs (accessed [today's date]).

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