Is SDHD p.Ser63Phe (c.188C>T) pathogenic?

SDHD p.Ser63Phe (c.188C>T) is classified Uncertain significance in SDHD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-14). AlphaMissense: ambiguous (0.5158); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with SDHD p.Ser63Phe (c.188C>T)?

SDHD p.Ser63Phe (c.188C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is SDHD p.Ser63Phe (c.188C>T) in the general population?

SDHD p.Ser63Phe (c.188C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SDHD p.Ser63Phe (c.188C>T)?

AlphaMissense predicts ambiguous (score 0.5158) — an in-silico prediction, not a clinical call.

SDHD p.Ser63Phe

c.188C>T · VCV3438810

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5158 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5158	ambiguous
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -13.30	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	28.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SDHD
Protein: p.Ser63Phe
Coding: c.188C>T
MANE Select: NM_003002
Type: single nucleotide variant
Location: chr11:112088885 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 63: an α-helix

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.Ser63Pro Uncertain significance ★★ ⚠ same residue
SDHD p.Ser63Cys Uncertain significance ★ ⚠ same residue
SDHD p.Ser63= Likely benign ★ 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
SDHD c.315-1G>A 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-ser63phe (accessed [today's date]).

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