Is SDHA p.Phe85fs (c.255del) pathogenic?

SDHA p.Phe85fs (c.255del) is classified Likely pathogenic in SDHA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). Very rare (popmax 0.00017%, nfe).

How common is SDHA p.Phe85fs (c.255del) in the general population?

SDHA p.Phe85fs (c.255del) is very rare (popmax 0.00017%, nfe) (gnomAD).

SDHA p.Phe85fs

c.255del · rs760710175 · VCV524020

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 0.00017%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.1	GERP -3.5
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,870 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,536 alleles · very rare exomes 3/1,461,204 · genomes 0/152,332 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,452
European (non-Finnish)grpmax	0.00017%	589,936

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SDHA
Protein: p.Phe85fs
Coding: c.255del
MANE Select: NM_004168
dbSNP: rs760710175
Type: Deletion
Location: chr5:224462 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB

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

Similar variants

SDHA c.1432_1432+1del Pathogenic/Likely pathogenic ★★ same type
SDHA c.457-2_457del Pathogenic/Likely pathogenic ★★ same type
SDHA c.63+2del Likely pathogenic ★★ same type
SDHA c.762_770+17del Pathogenic/Likely pathogenic ★★ same type
SDHA c.895+1del Likely pathogenic ★★ same type
SDHA p.Ala338fs Pathogenic ★★ same type
SDHA p.Ala582fs Pathogenic ★★ same type
SDHA p.Arg162fs Pathogenic/Likely pathogenic ★★ 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/sdha-p-phe85fs (accessed [today's date]).

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