Is SDHD p.Pro28Leu (c.83C>T) pathogenic?

SDHD p.Pro28Leu (c.83C>T) is classified Uncertain significance in SDHD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.1773); Very rare (popmax 0.000339%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHD p.Pro28Leu (c.83C>T)?

SDHD p.Pro28Leu (c.83C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is SDHD p.Pro28Leu (c.83C>T) in the general population?

SDHD p.Pro28Leu (c.83C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about SDHD p.Pro28Leu (c.83C>T)?

AlphaMissense predicts likely benign (score 0.1773) — an in-silico prediction, not a clinical call.

SDHD p.Pro28Leu

c.83C>T · VCV4161275

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1773 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1773	likely benign
REVEL	0.707	pathogenic-leaning
SaProt	LLR -8.30	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.1	GERP 1.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,656 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,712 alleles · very rare exomes 4/1,461,420 · genomes 0/152,292 · 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.Pro28Leu
Coding: c.83C>T
MANE Select: NM_003002
Type: single nucleotide variant
Location: chr11:112087887 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SDHD p.Pro28Arg Uncertain significance ★★ ⚠ same residue
SDHD p.Pro28Ser Uncertain significance ★★ ⚠ same residue
SDHD p.Pro28Thr Uncertain significance ★★ ⚠ same residue
SDHD p.Pro28His Uncertain significance ★★ ⚠ same residue
SDHD p.Pro28Ala Uncertain significance ★ ⚠ same residue
SDHD p.Pro28= Likely benign ★ same residue
SDHD c.170-1G>T Pathogenic ★★ same condition
SDHD c.170-2A>G Pathogenic/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-pro28leu (accessed [today's date]).

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