Is SDHD p.Ser68Arg (c.204C>A) pathogenic?

SDHD p.Ser68Arg (c.204C>A) is classified Uncertain significance in SDHD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-07). AlphaMissense: likely pathogenic (0.8547); Very rare (popmax 0.00134%, afr); Associated with pheochromocytoma.

What condition is associated with SDHD p.Ser68Arg (c.204C>A)?

SDHD p.Ser68Arg (c.204C>A) is associated with pheochromocytoma, Carney-Stratakis syndrome, Cowden syndrome 3 (ClinVar).

How common is SDHD p.Ser68Arg (c.204C>A) in the general population?

SDHD p.Ser68Arg (c.204C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about SDHD p.Ser68Arg (c.204C>A)?

AlphaMissense predicts likely pathogenic (score 0.8547) — an in-silico prediction, not a clinical call.

SDHD p.Ser68Arg

c.204C>A · rs9919552 · VCV1965210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8547 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pheochromocytoma

Computational evidence

Protein change
AlphaMissense	0.8547	likely pathogenic
REVEL	0.608	indeterminate
SaProt	LLR -12.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.61	GERP -4.3, phastCons 0.056
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	19.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00134% African / African-American · 1/74,888 alleles

Overall 6.2e-05% 1/1,612,572 alleles · very rare exomes 1/1,460,400 · genomes 0/152,172 · 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.Ser68Arg
Coding: c.204C>A
MANE Select: NM_003002
dbSNP: rs9919552
Type: single nucleotide variant
Location: chr11:112088901 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 68: an α-helix

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

Disease context

pheochromocytoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Carney-Stratakis syndrome Cowden syndrome 3

Similar variants

SDHD p.Ser68= Benign/Likely benign ★★ same residue
SDHD p.Ser68Thr Uncertain significance ★ ⚠ same residue
SDHD p.Ser68fs Pathogenic ★ same residue
SDHD p.Ser68Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHD c.170-1G>T Pathogenic ★★ same condition
SDHD c.170-2A>G Pathogenic/Likely pathogenic ★★ same condition
SDHD c.314+1G>A Pathogenic ★★ same condition
SDHD c.314+1G>T 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-ser68arg (accessed [today's date]).

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