Is SDHA p.Ser607Phe (c.1820C>T) pathogenic?

SDHA p.Ser607Phe (c.1820C>T) is classified Uncertain significance in SDHA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: ambiguous (0.4375); Very rare (popmax 0.00112%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHA p.Ser607Phe (c.1820C>T)?

SDHA p.Ser607Phe (c.1820C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is SDHA p.Ser607Phe (c.1820C>T) in the general population?

SDHA p.Ser607Phe (c.1820C>T) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about SDHA p.Ser607Phe (c.1820C>T)?

AlphaMissense predicts ambiguous (score 0.4375) — an in-silico prediction, not a clinical call.

SDHA p.Ser607Phe

c.1820C>T · VCV3438659

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4375 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4375	ambiguous
REVEL	0.738	pathogenic-leaning
SaProt	LLR -11.85	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	28.1	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 0.00112% South Asian · 1/89,172 alleles

Overall 6.24e-05% 1/1,603,292 alleles · very rare exomes 1/1,451,106 · genomes 0/152,186 · 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: SDHA
Protein: p.Ser607Phe
Coding: c.1820C>T
MANE Select: NM_004168
Type: single nucleotide variant
Location: chr5:254418 (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

Disease context

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

Similar variants

SDHA p.Ser607Pro Uncertain significance ★★ ⚠ same residue
SDHA p.Ser607= Benign/Likely benign ★★ same residue
SDHA c.1064+1G>T Likely pathogenic ★★ same condition
SDHA c.1064+2T>A Likely pathogenic ★★ same condition
SDHA c.1261-1G>A Likely pathogenic ★★ same condition
SDHA c.1261-2A>G Likely pathogenic ★★ same condition
SDHA c.151-1G>C Likely pathogenic ★★ same condition
SDHA c.151-2A>G 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/sdha-p-ser607phe (accessed [today's date]).

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